This article is a work
in progress and regularly updated as I study this topic.
Cardiovascular diseases (CVDs) are still the leading cause of death globally (OWID), but vary markedly by demographics and in relation to various lifestyle factors. In particular, in the second half of the 20th century, the seminal Seven Countries Study illuminated associations with diet, especially saturated fatty acids (SFAs), which at 50-year follow-up remain strongly associated with coronary heart disease mortality (n=16 cohorts, r=0.92) 1. Many other studies have further probed this relationship, and while some heterogeneity emerged, so has context. For instance, some prospective cohort studies and meta-analyses thereof fail to find independent associations with SFA intake 2; however, studies performing substitution analyses generally report that replacing sources of SFAs with (plant and marine-sourced) unsaturated fatty acids (UFAs) or complex carbohydrates lowers CVD risk and mortality (e.g. US 3–8, Europe 9–11 and pooled 12,13). Importantly, in the US it was also revealed that SFAs are typically replaced by refined grains and added sugars, which are also associated with CVD, potentially explaining prior null findings 4. In addition, dietary SFAs are also highly correlated with animal-sourced MUFAs (r=>0.8), which may have obscured favourable associations seen only with plant sources 7,8.
Paralleling the early observational research many randomised
controlled trials (RCTs) were also conducted, and which have been subject to
contemporary meta-analysis. Unfortunately these trials are mostly old and heterogeneous,
with some confounded by trans fats, making any pooled analysis highly sensitive
to the inclusion/exclusion criteria. Nonetheless, in the latest Cochrane meta-analysis
of 15 trials lowering SFAs significantly lowered CVD events—mainly being driven
by replacement with various PUFAs (n=8, RR=0.79, 95% CI 0.62–1.0) and carbohydrates
(n=5, RR=0.84, 95% CI 0.67–1.06)—but not CVD mortality (albeit with 75% less death
vs. event data), and with no evidence of harmful effects (e.g. diabetes and cancer)
14. And taking things further,
in a more stringent analysis restricted to 4 core trials with PUFA replacement (i.e. via seed oils, mostly soybean) the results get stronger (RR=0.71, 95% CI 0.62–0.81) 15. Supporting this favourable effect on hard
outcomes, a diverse literature of shorter RCTs show replacement of SFAs can
favourably modulate various biomarkers of risk and pathophysiology within blood lipids 16,17,
immuno-metabolic health 18–22
and endothelial/platelet activity 23–25.
Accordingly, lowering/replacing SFAs is a cornerstone of
dietary guidelines worldwide, along with refined grains and added sugars (FAO).
On the other hand, not everyone agrees 26–29.
Indeed as well as methodological difficulties with the observational and interventional data above, other nuances
include the specific SFAs/PUFAs, food source/matrix, dietary patterns, endogenous
biosynthesis (i.e. de novo
lipogenesis, DNL) and genotypes, all of which may confer differential effects. Moreover, mechanistic discussions are often limited to effects on plasma cholesterol,
limiting biological plausibility. These factors in mind, this post explores some
of the major biological pathways which may link dietary SFAs to CVD, as guided
by qualitative comparisons with UFAs in humans and supported by preclinical models
and mechanisms.
Atherogenesis
Most of the global CVD burden is due to ischemic vascular diseases
involving atherosclerosis—i.e. plaque buildup in the arterial wall. Atherosclerosis
starts in youth and progresses insidiously from initially superficial intima–media
thickening, which increasingly protrudes the lumen and reduces blood flow, to eventual
plaque rupture triggering thrombosis and infarction (e.g. heart attack or stroke).
Importantly, atherosclerosis is a systemic disease and systemic imaging of general
populations suggests subclinical plaque (i.e. stenosis or calcification) is
present in around half of asymptomatic individuals by midlife (e.g. US 30, Scotland 31,32, Spain 33,34
and Egypt 35), affecting many arteries
(esp. aorta–iliac) and correlating brain hypometabolism 33. At the cellular–molecular level, necropsy
studies show the progression from initial fatty lesion to advanced plaque involves
an increasing content of lipids, chiefly cholesterol (i.e. free and esterified)
and phospholipids (i.e. phosphatidylcholines and sphingolipids) 36, along with increasing leukocytes (esp.
macrophages), necrosis, fibrosis and calcification 37. The lipids are present in foam cells (i.e. as lipid
droplets) and extracellular deposits (e.g. lipoprotein aggregates and crystals),
while the simultaneous presence of apolipoprotein B (apoB) implicates plasma
lipoproteins as a source 36,38–40.
ApoB exists in 2 isoforms: apoB100, or the truncated
apoB48, with a single copy of either being attached to lipoprotein
particles exporting lipids from liver and intestine, respectively. In plasma the
apoB100-lipoprotein lineage dominates and is metabolised
systemically, whereby lipolysis of triglycerides (via lipoprotein lipase, LpL) drives
conversion of very-low-density lipoprotein (VLDL) to intermediate and
low-density lipoprotein (LDL). Meanwhile apolipoprotein A-I (apoA-I) collects and
esterifies cholesterol from the periphery maturing into high-density
lipoprotein (HDL), which transfers cholesteryl esters (CEs) to apoB-lipoproteins
(via cholesteryl ester transfer protein, CETP) generating increasingly cholesterol-rich
particles. Consequently, LDL is the major plasma cholesterol carrier, and with
its relatively long plasma residence (in the order of days), the major
apoB-lipoprotein (typically >90%). Ultimately, plasma cholesterol is largely
cleared by the liver (i.e. reverse cholesterol transport 41); indeed unlike triglycerides,
cholesterol is not fully catabolised by extrahepatic cells. Once in the
liver cholesterol can be recycled or excreted via bile, fates which may depend
upon the form of delivery. In humans the bulk of HDL-CEs (~70%) are transferred
to VLDL/LDL before hepatic uptake, however, uptake of free cholesterol,
particularly from HDL, may favour biliary excretion 42,43. Of note, some preclinical studies also
suggest hepatic channelling of cholesterol from LDL to plasma 44 and HDL to bile 45; although LDL can also mediate
macrophage efflux 46 and the
LDL receptor (LDLR) contributes substantially to faecal excretion in mice
(which are naturally CETP deficient) 47.
Conversely, in early atherogenesis lipids and apoB accumulate
in the arterial wall 48–50; in
human coronary arteries initial deposition occurred deep in intima (above internal
elastic lamina) and prior to macrophage infiltration 40. Susceptible sites (e.g. bends and
bifurcations) are typically exposed to turbulent blood flow and low shear
stress, and may exhibit increased lipoprotein permeability and/or retention 48,51. However, contrary to a passive
paracellular influx, free-LDL levels in normal arterial interstitial fluid may already
be higher than plasma 52, and lipoproteins
can readily cross the endothelium via transcytosis (i.e. active transport) 53,54, which is upregulated in human
plaque and murine atherogenesis via increased expression of scavenger receptor
class B type 1 (SR-B1) 55. Further,
plaque-prone regions exhibit diffuse intimal thickening, with increased content
of smooth muscle cells and extracellular matrix 40,56. Here apoB-lipoprotein binding to proteoglycans
(via electrostatic interaction) and LpL (acting as a bridge) may promote retention
40,48,49, while exposure to
various enzymes and oxidants may promote modifications, ultimately resulting in
aggregation, fusion and cholesterol crystallisation 39,57,58 (i.e. as per the ‘response-to-retention’
hypothesis).
A characteristic event of atherogenesis is the formation of
foam cells, which contain abundant CE-rich lipid droplets (creating their
‘foamy’ appearance) and may arise mainly from smooth muscle and myeloid cells
(i.e. monocytes and macrophages) 59,60.
This reflects a dichotomy: foam cells can remove and digest harmful extracellular
deposits liberating free cholesterol, with potential
for efflux from arteries, but when overloaded can themselves become a site of crystallisation,
inflammation and cytotoxicity 50,61,62.
In this regard, lipoprotein aggregates isolated from human plaques induce
accelerated macrophage uptake, greater cholesterol esterification 63 and inflammasome activation 39, while recovered apoA-I/HDL is
lipid-poor and pro-inflammatory, suggesting low acceptor/efflux activity 64. Reverse cholesterol transport from
tissues may also be mediated by lymph 52,54,65
and plaque progression is accompanied by expansion of adventitial lymphatics,
which in murine models can modulate atherogenesis 66. Beyond the arterial wall, atherosclerosis is also
associated with increased haematopoiesis 67;
even in apparently healthy people with subclinical atherosclerosis bone marrow
activity (i.e. labelled glucose uptake) correlated blood immune-inflammatory
markers and arterial activity (a surrogate of macrophage activity), suggesting
early links to atherogenesis 68.
Cholesterol
Since the early 1900s, and the work of Anichkov, it was
known feeding animals (e.g. rabbits) diets high in cholesterol can induce
atherosclerosis 69. Following
this, early epidemiological studies (such as the Seven Countries Study)
identified an association between serum cholesterol and CVD, later refined to
LDL-cholesterol (LDL-c) 70. To
this day, studies explicitly on low risk populations show LDL-c can independently
and linearly associate with subclinical atherosclerosis and CVD mortality 34,71–73; even when including markers of
LDL subspecies such as HbA1c (i.e. glycation), oxidised LDL (oxLDL) and lipoprotein(a)
34. Of note, in older cohorts
associations with all-cause mortality may be inverted by malnutrition 74. The causal role of LDL is supported
by drug trials (i.e. late life lipid-lowering) and more recent Mendelian randomisation
studies (i.e. lifetime lipids) 70,75.
However, CVD risk can track better with the cholesterol content of other
apoB-lipoproteins (e.g. VLDL, remnants and non-HDL) and indeed apoB itself 76,77, any of which can be discordant
from LDL-c, especially in situations of elevated triglycerides/VLDL and a preponderance
of small-dense LDL particles (i.e. pattern B), such as in metabolic disorders discussed
later. Of note, such small (vs. large) LDL particle profiles have also been
associated with greater risk 78,
although this disappears when controlling for particle count and other
confounders 79,80; indeed
small-dense LDL exhibits properties which may favour retention 81, albeit while carrying a smaller
cholesterol load 76. Further, recent
Mendelian studies also suggest the risk from apoB is mediated by non-HDL-c 82,83, which reflects the total
cholesterol content of all apoB-lipoproteins. On the other hand, the inverse
association between HDL-c and CVD seems non-causal, while cholesterol efflux
capacity from macrophage to HDL predicts risk better than HDL-c, suggesting HDL
function is more important 41.
In the Cochrane analysis of SFA-replacing trials above, meta-regression
of various factors showed that the greater the reduction in serum cholesterol,
the greater the reduction in CVD events, accounting for 99% of between-trial variation
14. Of these trials, STARS also
measured angiographic progression of CAD, which correlated intake of animal-sourced
trans fatty acids (TFAs) and SFAs (i.e. C14–18:0), and was also mediated via plasma
cholesterol (except C18:0) 84.
Indeed isocaloric replacement of complex carbohydrates with typical dietary SFAs
(i.e. C12–16:0) raises total/LDL cholesterol, whereas plant-based PUFAs (i.e.
C18:2/3) lower it, as established via 100s of metabolic ward studies 16 and formularised since the 1950s 85. This SFA/UFA dichotomy extends to low
carbohydrate/ketogenic diets 86–90.
Sensitivity is also maintained long-term; in the LA veterans trial a PUFA-rich
diet lowered serum cholesterol up to 8 years and with return to a conventional
diet it reverted within 1–2 weeks 91.
The cholesterol-raising effect of SFAs may be accentuated by dietary
cholesterol 92,93 and attenuated
in the case of cheese (vs. butter) 94.
Alongside cholesterol, SFA-rich diets also increase apoB 25,94–98 (for meta-regression see 17); more specifically, dairy fat/SFAs
can increase all VLDL–LDL particles (vs. seed oils/n-6 PUFAs) 95,99, large LDL (vs. MUFAs) 97 or medium–small LDL particles (vs.
MUFAs in people with pattern B) 98.
Whereas replacing SFAs with MUFAs or PUFAs did not significantly affect lipoprotein(a)
in a recent meta-analysis of RCTs 100.
Individual sensitivity to SFAs is also heterogeneous 25 and depends on genotype, most notably APOE variants 101,102; for instance, in the UK RISCK
study (n=389) carriage of an E4 allele
(vs. wildtype E3/E3) increased the cholesterol/apoB-lowering effect of replacing
SFAs with low GI carbohydrates, while
reducing that of MUFAs 101.
The atherogenic effect of cholesterol and SFAs is also
evident in animal models such as non-human primates 15. For instance, in African green
monkeys fed cholesterol-containing diets with 35% fat for 5 years, safflower
oil/n-6 PUFAs (vs. palm oil/SFAs and safflower oil/MUFAs) reduced atherosclerosis,
which correlated LDL-c and particle weight/size 103. Across various genetic mouse models replacement of SFA-rich
diets with seed oils/n-6 PUFAs can also reduce hyperlipidemia and
atherosclerosis (in spite of increased inflammation) 104–107. Further, in normal and APOE–/– mice injected with
labelled human LDL a coconut oil/SFA-rich diet (vs. normal chow) increases arterial
selective uptake of CEs, correlating plasma cholesterol, arterial LpL and
atherosclerosis 108; whereas in
LDLR–/– mice incremental
replacement with fish oil/n-3 PUFAs reduced hyperlipidemia (esp. cholesterol), arterial
macrophages/LpL and aortic lesions 109.
In APOE–/–mice hypercholesterolemic
diets also rapidly (within days) induce foamy-inflammatory monocytes which
infiltrate nascent lesions 110;
in LDLR–/– mice this was
reduced by replacing dairy fat/SFAs with plant-based UFAs (i.e. extra-virgin
olive oil and nuts) 111. Note
however, in both monkeys and mice oleic/MUFA-rich diets can induce similar
atherosclerosis to SFAs (vs. n-6/n-3 PUFAs), which especially correlates LDL
particle size 103,107. In mice
this requires ACAT2 (aka. SOAT2) 107
which synthesises oleate-rich CEs for apoB-lipoproteins 112 and mediates LDL proteoglycan binding
113 and aggregation 114; contrasting the more favourable
effects in humans of MUFA-rich diets on LDL size 97,98 and binding 113,115.
Importantly, animals may be fed higher cholesterol 113,116, express higher ACAT2 (e.g. monkeys and rats) 42,117 or have LDLR/apoE knockout (e.g.
mice) 69, any of which might
increase MUFA sensitivity; while effects in humans may depend on food source 7,8, olive oil quality 118 and APOE variants 101.
Early cell studies suggested lipoproteins must first be
modified in some way (e.g. oxidised) to promote atherogenesis—an enduring dogma.
However, while lipoprotein modifications have many important effects discussed
herein, this may not be strictly true. High levels of native LDL can
dose-dependently induce macrophage foam cell formation in a non-saturable
manner via receptor-independent fluid-phase pinocytosis 119 and selective CE uptake 46; as well as proteoglycan secretion 120. LDL transcytosis through endothelium
is also dose-dependent 121, and
high or prolonged exposures can induce endothelial dysfunctions (e.g. adhesiveness
122, nitric oxide 123, permeability 124,125 and senescence 126), which may involve cholesterol
itself, as discussed later (and reviewed in 53,61,127). In particular, native LDL treatment of human
endothelial cells for several days induces lipid droplets and cholesterol
crystals, which are reduced by cAMP stimulation 128. Cholesterol crystals can impair endothelial function
(e.g. vasodilation, leukocyte barrier and cell survival) 128,129, while activating endothelial and
macrophage NLRP3 inflammasomes, which release cytokines recruiting immune cells
130 and inducing LDL
transcytosis (via LDLR) 131. In
hyperlipidemic mice on a western (sugar/SFA-rich) diet cholesterol crystals
form within a week (i.e. before macrophage infiltration and neointima formation),
while stimulation of cAMP (in inflamed endothelium) 128 or deficiency of NLRP3 (in bone
marrow) can suppress early atherosclerosis 130.
Thus native LDL is not innocuous, but may be decoupled from atherogenesis via
modulation of endothelial and immune activity, the physiological states of which
may determine individual susceptibility. Counterplay with HDL may also be
important and seems rarely tested in
vitro 132.
How does fat saturation modulate plasma cholesterol? In
human trials SFA-rich diets decrease LDL catabolism 133 and PBMC LDLR expression 25,95,96, which inversely correlates
apoB/LDL-c 96, suggesting
decreased tissue uptake. In animal models this depends upon dietary cholesterol
116,134,135. Along this line,
early hamster studies suggested UFAs (i.e. C18:1/18:2 UFAs vs. C12–16:0 SFAs) are
better substrates for ACAT-dependent cholesterol esterification and so may lower
free cholesterol in regulatory domains of the endoplasmic reticulum (ER) to induce
SREBP-dependent LDLR expression 116.
However, in monkeys and rodents MUFAs stimulate the greatest hepatic CE
synthesis/secretion 136,137
and LDLR expression 116; and
in LDLR–/– mice MUFAs and
SFAs elevate plasma cholesterol over PUFAs 104,106,
which was largely abrogated by ACAT2 deletion 107. Thus ACAT has specificity for oleate, yet plasma lipids
are lowest with linoleate. Moreover, in a human tracer study (using
radiolabelled mevalonic acid and free cholesterol) there was an absence of
tissue CEs appearing in plasma, consistent with lower ACAT expression 42. Rather human plasma CEs are typically
rich in n-6 PUFAs (i.e. C18:2 > C18:1 > C16:0), in contrast to triglycerides
and phospholipids 87, and consistent
with the specificity of LCAT, which mediates cholesterol esterification in
plasma lipoproteins via transfer of a fatty acid from phosphatidylcholine, favouring
sn-2 position C18:2 138,139. Dietary fats can modulate plasma
phospholipid composition, and in some human and rodent studies also endogenous LCAT activity (i.e. n-6 PUFAs
> MUFAs > SFAs) 140–142,
although other findings are less consistent 140,143,144. In addition, overexpression of human LCAT in
animals such as transgenic rabbits (which also naturally express CETP) typically
elevates HDL-c, and may lower apoB/LDL-c via the LDLR 145, although large increases in enzyme quantity
(vs. substrate modulation) may have different effects. Regardless, in humans most
HDL-CEs are transferred to VLDL/LDL and fatty acid composition may affect cell binding.
For instance, in men with hypercholesterolemia a 6-week walnut/PUFA-rich diet
(vs. olive oil/MUFAs) increased LDL n-6/n-3 PUFA content and hepatocyte
association in vitro, especially in
those showing lower LDL-c and correlating C18:3 in core lipids (i.e. TGs+CEs r2=0.41) 146. Besides LDL, PUFAs (vs. SFAs) may
lower HDL-c in humans via decreased apoA-I production 147, whereas in other animals via increased
HDL clearance 143,148.
Does fat saturation affect systemic sterol balance? Early human
studies varied in their methods and results, but PUFAs (vs. SFAs) more often increased
sterol excretion (i.e. faecal neutral sterols and/or bile acids) 149,150 and cholesterol biosynthesis (i.e.
deuterium incorporation) 151,
which seem highly related 152.
The former may particularly occur at high (vs. low) cholesterol intake and under
non-steady state in normal adults, but less so in familial hyperlipidemia,
despite still lowering plasma cholesterol; thus tissue redistribution has been
suggested 149, as seen in
guinea pigs (on low cholesterol diets for 6–7 weeks) 153. The sterol balance technique has
also been adapted to ileostomy subjects where isocaloric fat substitution with
oils rich in PUFAs or MUFAs acutely increased net sterol excretion (within 2–4
days) 154, which may be partly
attributable to their phytosterol content 155
(as controlled for in several earlier studies 149,150,156). Some studies also implicate upstream changes to
reverse cholesterol transport. For instance, healthy adults (n=122) with higher
insulin responses or SFA intake (>10% kcal) had lower ABCA1-dependent efflux
to HDL (independent of HDL-c); tested in mice an obesogenic diet rich in palm
oil/SFAs or sunflower oil/MUFAs lowered ABCA1-dependent efflux, but only the
former lowered liver–faeces cholesterol transport (in relation to weight gain)
157. Further, replacing
butter/SFAs with seed oils/n-6 PUFAs (without controlling for dietary sterols)
for 8 weeks induced serum bile acids as well as PBMC transcripts related to
efflux (LXRα and ABCG1) and influx (LDLR) (also replicated in 25);
in multivariate analysis (incl. lipids, metabolites and gene expression) the
most important explanatory variable was LXRα
95. After just 3 days this intervention also induced faecal Bifidobacteria and Lachnospiraceae, the latter negatively correlating total
cholesterol (r=–0.511); as a potential mechanism the authors
invoked other evidence suggesting bacterial conversion of faecal cholesterol to
coprostanol may prevent reabsorption 158.
In summary, dietary UFAs (vs. SFAs) may lower plasma cholesterol largely
by increasing LDL uptake (by liver and elsewhere), and concomitant with sterol efflux/excretion
95,135.
Metabolic
Recent decades have seen an epidemic of obesity and overweight-related
metabolic disorders, including non-alcoholic fatty liver disease (NAFLD),
metabolic syndrome (MetS) and type-2 diabetes (T2D), which are strongly associated
with one another and CVD. In people with subclinical atherosclerosis bone
marrow activation was also associated with MetS and its components (but not
LDL-c), even in those with lower systemic inflammation (i.e. below median CRP) 68. Such metabolic disorders have shifted
the typical lipid profile toward increased serum triglycerides and low HDL-c 159, with attendant small-dense LDL (aka.
‘atherogenic dyslipidemia’) 81.
Linking this profile, high hepatic triglyceride status drives overproduction of
VLDL1 (enriched in apoC-III), triglyceride transfer to LDL (via
CETP) and lipolysis to small-dense LDL (via hepatic lipase); and a similar
process may lower HDL-c 81,160.
Importantly, triglyceride-rich lipoproteins (TRLs) also constitute
non-LDL/HDL-associated ‘remnant cholesterol’ 161, but may play a potent causal role in atherosclerosis
beyond their cholesterol content (and LDL) as suggested by Mendelian 83 and preclinical studies 162.
Regarding diet, in meta-regression of RCTs isocaloric
replacement of carbohydrates with SFAs can lower fasting triglycerides, but UFAs
more so (i.e. C18-PUFAs > MUFAs > SFAs) 15,17. Further, in overweight people with a small LDL
particle profile (i.e. pattern B), a dairy/SFA-rich diet (vs. MUFAs) for 3
weeks non-significantly increased triglycerides (p=0.06), but significantly increased apoB, medium–small LDL
particles and hepatic lipase activity, and CETP activity independently
correlated medium and small LDL 98.
While effects on postprandial lipemia seem equivocal (reviewed in 163), SFA-rich meals (i.e. palm oil and
cocoa butter vs. various UFAs) induced apoE expression on TRLs; tested in vitro this increased hepatocyte LDLR
binding causing competitive inhibition of LDL uptake 164, and more so in those with an APOE4 allele 165 (itself associated with both CVD and Alzheimer’s). Of note, in mice a
cocoa butter/SFA-rich diet (not MUFAs or fish oil/n-3 PUFAs) also induced
amyloid-beta (Aβ) in gut enterocytes
and plasma TRLs 166,167,
blood–brain barrier (BBB) dysfunction and Aβ transport to the brain 168;
if corroborated in humans this could underlie the epidemiologic association
between SFA intake and Alzheimer’s 169.
Reciprocally, dementia and plasma Aβ40 are associated with CVD 170, while Aβ40/42
binding to native or modified LDL enhanced foam cell formation in vitro 171. In healthy adults high fat meals (vs. low fat) can
also induce foamy-activated monocytes in association with postprandial TRLs 172–174 and VLDL lipid saturation 175; tested in vitro TRLs from meals high in SFAs (vs. MUFAs and n-3 PUFAs) induce
greater immune cell apoB48 (chylomicron) receptor expression, lipid
accumulation and activation 176–178,
and coronary smooth muscle cell invasion 179.
Similarly, TRLs and their lipolysis products (mainly fatty acids) from LDLR–/– mice on a diet rich
in dairy fat/SFAs (vs. extra-virgin olive oil and nuts) induced more monocyte
lipid accumulation 111. As
chylomicrons are depleted of triglycerides they become remnant particles rich
in cholesterol, which may particularly enter the hepatic regulatory pool to
lower LDLR expression 44. However,
enrichment of chylomicron remnants with SFAs (vs. various UFAs) may lower hepatocyte
LRP1 gene expression and uptake 164,
while inducing macrophage lipid accumulation 180. Therefore the SFA content of TRLs may contribute to
their atherogenicity.
More broadly, dietary fat quality may differentially affect systemic
fat oxidation and storage. In human fatty acid tracer studies whole-body
oxidation of typical dietary SFAs is lower than MUFAs and PUFAs, consistent
with animal and cell studies 181,182.
Also, short-term low carbohydrate diets favouring UFAs (vs. SFAs) induce higher
serum ketones 86–88 (and improve
long-term seizure control 89),
consistent with preclinical studies on hepatic β-oxidation and ketogenesis 183,184. Furthermore, in short-term imaging trials on normal 185 and overweight adults SFAs induce more
liver fat (i.e. intrahepatic triglycerides) under isocaloric (i.e. butter/SFAs
vs. sunflower oil/n-6 PUFAs 186)
or hypercaloric conditions (i.e. palm oil/SFAs vs. sunflower oil/n-6 PUFAs 185,187; or various SFAs vs. UFAs and
sugars 188,189), while
increasing the plasma SCD index (a putative marker of hepatic desaturation/DNL)
185–187 and adipose lipolysis 189, both of which may increase hepatic fatty
acid availability. And inversely, in a trial on NAFLD patients randomised to
specific diets (i.e. standard care, low carbohydrate or intermittent fasting) for
12 weeks, reductions in liver fat and stiffness correlated with increased plasma
n-6 PUFAs and decreased intake of SFAs/MUFAs, respectively 190.
Cardiometabolic diseases typically involve insulin
resistance and consequent hyperglycaemia, which is itself associated with CVD 191; even in the nondiabetic PESA cohort
HbA1c (i.e. monthly glucose control) independently correlated the presence and
extent of subclinical atherosclerosis 34.
Moreover, a 1-year RCT with insulin-stimulating drugs in T2D induced regression
of carotid intima-media thickness (cIMT) in relation to postprandial glucose 192. Mechanistically, hyperglycaemia can induce
oxidative-inflammatory activity and endothelial dysfunction 191, while glycation of LDL increases
arterial proteoglycan binding 193,194.
Insulin itself also normally suppresses VLDL-triglyceride secretion and promotes
apoB catabolism and clearance 160,195,
and may modulate many atherogenic cells 196,197.
Glucose-insulin homeostasis is affected by dietary fat quality; in a systematic
review and meta-analysis of controlled feeding trials isocaloric replacement of
SFAs with PUFAs improved insulin sensitivity and glucose control 18. Further, in people spanning the range
of insulin sensitivity (i.e. athletes–lean–obese–T2D), intramuscular accumulation
and subcellular localisation (i.e. sarcolemma and organelles) of saturated triglycerides
198 and sphingolipids/ceramides
199 correlate insulin
resistance, while SFA intake was increased in T2D 198. Accordingly, in some trials on healthy adults a higher palmitate/SFA
intake (vs. oleate/MUFA) for 2–3 weeks 200,201,
or as a single bolus 202, induced
blood/muscle sphingolipids/ceramides and suppressed glucose metabolism and
insulin sensitivity. Also, in trials on overweight adults overfeeding SFAs from
mixed sources (vs. UFAs or sugars) for 3 weeks 189, or palm oil/SFAs (vs. sunflower oil/n-6 PUFAs) for 8
weeks 187, increases multiple plasma/LDL
sphingolipid species (opposite to PUFAs), paralleling induction of insulin
resistance and liver fat. And inversely, in obese adolescents on a 1-year
multidisciplinary intervention, SFA reduction correlated a decreased insulin
and increased adiponectin/leptin ratio, which itself negatively correlated cIMT
203. Of note, in mice and
human cells palm oil/SFAs (vs. olive oil/MUFAs) also induced intestinal insulin
resistance via ceramide, thereby impairing the ability of insulin to inhibit
triglyceride secretion and linking to postprandial hypertriglyceridemia 204.
Besides glucose metabolism, sphingolipids may have more
direct effects on atherogenesis. Indeed alongside cholesterol, atherosclerotic
plaque was long known to contain sphingolipids 36. More recently various sphingomyelins and ceramides were
identified and associated with plaque inflammation and apoptosis 205, while serum ceramides (esp. Cer16:0,
Cer18:0 and Cer24:1) predict CVD risk independent of conventional risk factors
(incl. apoB) 206. Serum
ceramides are particularly elevated in obesity and T2D 206; although LDL ceramides were only
elevated in the latter and in preclinical models induce macrophage activation
and muscle insulin resistance 207,
involving mitochondrial dysfunction 208.
Further, LDL can deliver ceramide to endothelial cells 209, where it can mediate apoptosis 209, suppress nitric oxide (i.e. eNOS) 210 and increase the uptake and retention
of oxLDL 211. Moreover, aggregated
LDL from human plaques was highly enriched in ceramide, a product of sphingomyelin
cleavage by SMase, which promotes LDL aggregation and fusion in vitro 57. Accordingly, LDL susceptibility to aggregation, as
induced by human S-SMase, was associated with CVD death independent of traditional
markers (e.g. LDL-c) and activated macrophages and T cells in vitro (contrasting oxLDL) 114.
LDL aggregation was also related to the surface/core lipidome (esp. ↑ sphingolipids/ceramides vs.
phospholipids) and favourably modified by a ‘Healthy Nordic diet’ (incl. ↓ SFA/PUFA ratio; Fig. S5) or
lipid-lowering drug (i.e. PCSK9 inhibition) 114. In a subsequent trial on overweight adults, overfeeding by
1000kcals/day as SFAs from mixed sources for 3 weeks induced LDL sphingolipids
and aggregation, while UFAs (i.e. 57% MUFAs, 22% PUFAs) lowered LDL
proteoglycan binding (and apoE) and sugars were without effect 115. A further study including liver
biopsies reported that LDL aggregation and lipid composition correlates the liver
lipidome, implicating hepatic sphingolipid metabolism in LDL composition 212. In rodent models high fat diets
induce de novo sphingolipid synthesis
(i.e. via SPT) and salvage pathway turnover increasing the generation of
long-chain ceramides in liver, plasma and elsewhere, while the SPT inhibitor
myriocin ameliorates atherosclerosis (reviewed in 213). Also, in LDLR–/–
mice a diet rich in cholesterol and dairy fat/SFAs induced macrophage S-SMase, which
acts on serum LDL to increase ceramide and susceptibility to aggregation and
oxidation 214.
Oxidation
OxLDL is present in plaques and plasma where it’s associated
with CVD 215,216, although not
always independently of apoB (e.g. CHD 217
and MetS 218), likely due to
4E6 antibody cross-reactivity 219.
On the other hand, oxidised phospholipids on apoB100 (oxPL–apoB) are
independently associated with CVD and mainly carried by lipoprotein(a), an LDL
variant; indeed oxLDL donates its oxPL to lipoprotein(a) in vitro 219.
OxLDL normally represents a very small fraction of plasma LDL 220 and increases preceding progression
and regression of experimental atherosclerosis, suggesting exchange with plaque
221; similar to oxPL–apoB 219. Oxidation of LDL in vitro is typically achieved by
incubation with copper (Cu2+) sulfate solution or arterial cells
cultured in media containing transition metals, which induce 1-electron
oxidations via Fenton chemistry. This enhances its pro-atherogenic
endothelial/inflammatory effects (e.g. eNOS 61, CCL20 222,
EPCs 127 and HSPCs 67) and induces macrophage uptake via
scavenger receptors 216. Here
it induces lipid droplets, which may be limited by defective lysosomal
processing 119, but also
lysosomal crystals and NLRP3 activation 130,223.
As the major transition metal in vivo,
iron (Fe2+) dysregulation may particularly promote oxidation during
plaque haemolysis 224.
Moreover, many studies also report that human plaques have increased expression
of inducible nitric oxide synthase (iNOS) 225–229
and myeloperoxidase (MPO) 230
(which employ a central heme-iron active site to generate oxidants), while
recovered LDL and apoA-I/HDL are highly enriched in their 2-electron protein
oxidation products (i.e. nitrotyrosine and 3-chlorotyrosine, respectively) 231,232, implicating immune-dependant
redox modifications 233. These
oxidations are not blocked by serum (unlike copper oxidation) and resulting NO2–LDL
stimulates macrophage uptake and cholesterol loading via scavenger receptor
CD36 234,235. Note however, in
early studies LDL isolated from human aortic fatty streaks and plaques was not
sufficiently oxidised for receptor-mediated uptake, which instead was increased
in a non-saturable manner attributable to aggregates 63. Indeed LDL aggregation greatly
increases macrophage uptake by receptor-independent endocytosis 46,63 and CE accumulation beyond native
or oxLDL 236,237. Further,
mildly oxidised LDL inhibits native LDL-induced foam cell formation 238, although such particles tend to
aggregate 57 and still induce
macrophage crystals 130,223,
so may contribute in this way 63.
As above, apoA-I/HDL isolated from human plaques is lipid-poor and oxidised by
MPO, wherein modified tryptophan residues inactivate its ABCA1-dependent
acceptor activity 232,239.
Of lipids PUFAs are particularly susceptible to oxidation,
of which linoleic acid (C18:2n-6) is most abundant in LDL and plaque CEs.
Accordingly, electrospray MS/MS revealed a substantial proportion of peripheral
plaque CEs are oxidised, and cholesteryl linoleate to the greatest extent 240. This may occur despite normal levels
of the major lipophilic antioxidant α-tocopherol
(aka. vitamin E) 241,242; i.e.
contrasting typical conditions in vitro
and consistent with failed antioxidant trials 233. Importantly, while under strong copper-oxidising
conditions α-tocopherol acts
as a chain-breaking antioxidant and underlies the lipid oxidation lag phase,
under more mild conditions the α-tocopherol
radical can initiate lipid oxidation 243,
or when there are insufficient regenerative co-antioxidants (e.g. CoQ10
and carotenoids) 244; and α-tocopherol does not block
iNOS/MPO-derived oxidants 241.
Moreover, in a systematic analysis of human aortic lesions from early to
end-stage disease accumulation of cholesterol (stages II–III) and CEs (stages
IV–V) preceded their major oxidised derivatives (i.e. 27-hydroxycholesterol and
CE hydroperoxides/hydroxides, respectively), while α-tocopherol and CoQ10 levels remained stable,
consistent with mild and enzymatic oxidative responses to lipid accumulation 245. At least some of this may even be
adaptive; for instance, 27-hydroxycholesterol is produced by sterol
27-hydroxylase and may facilitate efflux, especially when HDL is deficient 246; and 13-hydroxy-linoleic acid (aka.
13-HODE) can be produced by 15-LOX-1 and stimulates cholesterol efflux to
apoA-I via a PPAR–LXRα
pathway 247. More recent
high-resolution imaging of advanced carotid plaques has also revealed that
oxidised CEs co-localise with sphingomyelin in the necrotic core 248. Of potential relevance, 1-electron
oxidation of LDL-c generates 7-ketocholesterol, which in macrophages inhibits
lysosomal SMase causing accumulation of sphingomyelin–cholesterol particles 249, and also dose-dependently induces
cholesterol crystals 250.
Regarding diet, in various short-term trials plant-based MUFA-rich
diets can lower LDL and HDL oxidation, and susceptibility to copper oxidation (i.e.
lag time and/or rate) and monocyte adhesion in
vitro, correlating oleate/linoleate ratios and opposite to n-6/n-3 PUFA-rich
diets 251–253. However, this
doesn’t parallel favourable associations between PUFAs and hard outcomes or factor
other important precursors to arterial oxidation in vivo, such as lipoprotein retention and inflammation, as above. Accordingly,
in men 91, monkeys 103 and mice 105 n-6 PUFA-rich diets increase linoleate/oleate ratios in
plasma and plaques, and oxidation in
vitro 103 and in vivo 105, yet are protective. The long-chain n-3 content of
advanced carotid plaques is also increased by supplementation and correlates
greater stability and lower inflammation, consistent with anti-inflammatory
effects 254,255. Furthermore,
the food matrix is also important. For instance, in healthy adults an n-6/n-3
PUFA-rich walnut meal (i.e. 59g fat, 42g PUFAs) increased postprandial
antioxidant capacity and lowered MDA (5-hour AUC) and oxLDL (at 2 hours) 256, while longer trials show enrichment
of PUFAs with preservation of oxidation status 257,258, alongside many other cardio-protective effects
(reviewed in 259). Conversely,
red meat and heme-iron intake are associated with CVD 260–263 and can promote lipid oxidation
during digestion 264. For
instance, in humans and mice red meat ingestion induced postprandial plasma
lipid oxidation and corresponding LDL–MDA modification, which was greatly
inhibited by polyphenols 265,266;
and in gastric models olive oil/MUFAs inhibited red meat/iron-induced lipid
peroxidation, opposite to fish oil/n-3 PUFAs 267. Of note, in a unique RCT comparing oxidised vs. high
quality fish oil, only the latter lowered apoB-lipoproteins 268; indeed excessive PUFA oxidation may eventually
abrogate any benefits. SFA-rich diets (vs. carbohydrates or MUFAs) may also
increase LDL oxidation in vitro in
relation to LDL MUFA/PUFA ratios 252,253
and APOE promoter variants 102. Some studies also implicate dairy
fat. For instance, in healthy adults a high fat milkshake (vs. low fat) induced
pathological RBC remodelling and foamy monocytes, while elevating plasma and
RBC-bound MPO in association with impaired flow-mediated dilation (FMD) and
chlorination of HDL; tested in vitro
major cow milk fatty acids (i.e. oleic or palmitic acid) induced MPO release by
monocytes and uptake by porcine arteries 172.
In mice a diet rich in dairy fat/SFAs also elevated oxidised HDL and LDL, while
replacement with soybean oil/PUFAs (i.e. ~5:1 of n-6:n-3) enhanced HDL
antioxidant activity 269; and
in another study replacement with olive oil and nuts lowered monocyte oxLDL
uptake and CD36 expression, which was modulated correspondingly by TRLs from
each diet 111.
Lipopolysaccharides
In 1999 the Bruneck (prospective) study of older Italians (n=516;
age 50–79 at baseline) published the first evidence of an association between
circulating levels of lipopolysaccharide (LPS), an outer membrane component of Gram-negative
bacteria, and early carotid atherosclerosis, which was independent of
traditional vascular risk factors (incl. apoB) except smoking 270. Nowadays many studies support a link
with cardiometabolic disease and athero-thrombosis (e.g. reviews 271–273). LPS is the canonical ligand for
toll-like receptor 4 (TLR4), which stimulates innate immunity and primes the
NLRP3 pathway 39,130,223;
although depending on source/structure, it can act as an agonist or antagonist (e.g.
E. coli and Bacteroides, respectively) 274.
In mouse models of endotoxemia platelet TLR4 triggers neutrophil extracellular
traps (NETs) to ensnare bacteria in liver sinusoids and pulmonary capillaries 275,276; although in APOE–/– mice LPS-induced neutrophils also promote monocyte
recruitment and aortic atherosclerosis 277,278,
and increase carotid plaque MPO and instability 279, consistent with human samples 278,279. In particular, E. coli-LPS was present in human carotid
plaques (esp. necrotic core; Fig. 1A) and associated with enlarged macrophages;
tested in vitro similar LPS levels incubated
with monocytes induced TLR4-dependent NADPH oxidase 2 (Nox2) and oxLDL 280. Further, carotid LPS correlated
plasma LPS (r=0.668), which
correlated soluble TLR4 and serum zonulin (a marker of intestinal permeability)
280; with similar blood marker
relationships reported in other populations 281–283. Accordingly, several gut microbiome studies on
people with CVD find elevated Gram-negative Enterobacteriaceae
(e.g. E. coli and Klebsiella) and decreased
butyrate-producing bacteria (e.g. Roseburia
and Faecalibacterium) 284–286. Butyrate is the archetypal beneficial
short-chain fatty acid (SCFA) and ameliorates atherosclerosis in APOE–/– mice by lowering gut
permeability and endotoxemia 287
and inducing ABCA1-dependent cholesterol efflux 288. Several human studies also find depletion of Bacteroides spp. 284,289,290, which when administered to APOE–/– mice also lowered atherosclerosis
and gut/blood LPS 289.
The systemic transport of exogenous (microbial) lipids is
analogous to that of endogenous lipids. Indeed in blood both LPS and
Gram-positive lipoteichoic acid (LTA) are largely bound to lipoproteins 291, transferred from HDL to LDL (via LBP
and PLTP) 292,293, and removed
predominantly via the hepatic LDLR (in humans) 294,295. A single LDL particle can bind many LPS molecules
with only minor changes to its composition 296;
such binding sequesters the lipid A region within the phospholipid monolayer
and hepatic uptake is apparently non-toxic 294,295.
Accordingly, human PCSK9 loss-of-function variants, which increase LDLR
expression and lower plasma LDL, were associated with improved sepsis survival
and lower LPS-induced inflammation in
vivo 297, contrasting the
situation in LDLR–/– mice 297,298. Importantly, lipoproteins may
also carry bioactive LPS into other tissues to elicit inflammation (e.g.
endothelium 299,300, adipose 301,302 and brain 303,304), which would presumably be facilitated
by slower hepatic uptake. In particular, LDL–LPS complexes formed in vitro acquire a negative charge and
have increased binding and accumulation in arterial wall and macrophages 305. Here LPS can activate endothelium
and monocyte chemotaxis 290,299,300,
induce smooth muscle synthesis of elongated proteoglycans (equal to traditional
agonists) 306, increase LDL
susceptibility to oxidation (by copper, endothelial and smooth muscle cells) 307, and stimulate macrophage oxLDL
uptake and foam cell formation 308.
Moreover, in humans and rodents LPS impairs total (i.e. macrophage–faeces) reverse
cholesterol transport at multiple steps 309;
in part via induction of MPO/SAA 310
and suppression of ABCA1 311.
In another prospective study on people with atrial
fibrillation (n=912; mean age 73.5), blood LPS was associated with major CVD
events, platelet activation and LDL-c, and negatively with Mediterranean diet
scores (esp. fruit and legumes) 312.
In systematic reviews dietary fat quality also affects gut microbiota 22 and plasma LPS 21. Of interest herein, habitual SFA
intake has been associated with bile-resistant sulfide-producing genera such as
Bilophila (family Desulfovibrionaceae) in faeces 313 and colonic mucosa 314. Also, in a 3-week trial on
overweight adults (similar to those above 115,189),
overfeeding SFAs increased faecal Gram-negative Proteobacteria (mainly
via Desulfovibrionaceae), while UFAs increased butyrate-producing
bacteria (i.e. Lachnospira, Roseburia and Ruminococcaceae spp.) 188,189;
similarly, replacement of butter/SFAs with margarine/n-6 PUFAs for just 3 days induced
Bifidobacteria and Lachnospiraceae 158. In mice dairy fat/SFAs (vs.
safflower oil/n-6 PUFAs) induce secretion of taurine-conjugated bile acids to
support expansion of Bilophila wadsworthia (a sulfite-respiring
bacterium) 315, which in turn lowers
colonic butyrate and induces LPS
biosynthesis and translocation 315–317.
Moreover, in a systematic review of RCTs assessing the effect of fat quality on
metabolic endotoxemia, SFA-rich meals can increase postprandial LPS in both
normal and overweight subjects 21.
For instance, in healthy adults a 35% fat porridge meal made with coconut
oil/SFAs increased postprandial LPS (vs. fish oil/n-3 PUFAs), but not serum
cytokines, whereas grapeseed oil/n-6 PUFAs did not 318; although an intermediate effect was significant in a prior
pig study 319. Further, in
other trials dairy fat (vs. carbs, MUFAs and n-3 PUFAs) increased postprandial
LPS alongside PBMC activation (incl. TLR2/4) and
endothelial adhesion markers 320–322;
an effect quicker in obesity 322
and still present after 12 weeks of a SFA-rich diet 321. Also, in people with impaired
fasting glucose postprandial LPS correlated apoB48 (i.e. chylomicrons)
and oxLDL, which was suppressed by substituting cheese/SFAs for extra-virgin
olive oil/MUFAs, and inversely correlated plasma polyphenols; tested in vitro equivalent LPS levels incubated
with platelets induced TLR4-dependent Nox2 and oxLDL 323. Accordingly, in preclinical studies
LPS absorption can occur via chylomicrons 324,
which deliver bioactive LPS to lymph 325.
Short-term controlled-feeding crossover trials on healthy adults also report
that lowering a habitual western diet palmitate/oleate ratio (from ~1:1 to 1:10)
lowers LPS-induced cytokine secretion in
vitro 326–328. Whereas n-6 PUFAs (vs. SFAs) induced PBMC TLR4 expression
in humans 95 and increased macrophage
LPS sensitivity in mice 106,
although this may be moderated by long chain n-3 PUFAs 329, implicating n-6/n-3 balance. Nevertheless,
SFA-rich diets may increase LPS biosynthesis, translocation and sensitivity,
while potentially lowering LDLR-mediated hepatic clearance.
In human and experimental fatty liver, hepatocyte LPS is also
increased, associated with immune-inflammatory markers 330 and implicated in pathogenesis (e.g. reviewed
in 331). As above, SFA-rich
diets can induce liver fat; in particular, one group found this occurred with increased
adipose lipolysis and inflammation (i.e. tissue transcriptome), blood liver
enzymes, ceramides and endotoxemia (i.e. LBP/CD14 ratio), faecal Proteobacteria 189 and baseline abundance of Bilophila 188. Similarly, in mice an obesogenic diet rich in palm
oil/SFAs (vs. sunflower oil/MUFAs) induced adipose macrophages and hepatic
inflammation, while enriching small HDL in acute-phase proteins (incl. SAA) and
lowering liver–faeces cholesterol transport 157, akin to low-dose LPS 311. Further, Bilophila
wadsworthia aggravated dairy fat/SFA-induced metabolic dysfunctions and
steatosis, while suppressing microbial butyrate and inducing LPS 316. In the postprandial setting, in
young healthy adults a single coconut oil/SFA-rich meal suppressed HDL
anti-inflammatory activity (on TNFα-activated
endothelial cells) and FMD, while the former improved after safflower oil/n-6
PUFAs 332. A single bolus of
palm oil/SFAs (equivalent to a SFA-rich meal) also induced whole-body/adipose/liver
insulin resistance, while elevating intrahepatic triglycerides and plasma free
fatty acids, but not inflammatory markers; although a parallel mouse study with
hepatic transcriptome analysis revealed evidence of LPS/TLR signalling 333. Of interest here, fat-induced LPS
absorption may not only involve chylomicrons, but a more rapid and dominant
portal vein pathway 334,
wherein intestinal secretion of HDL3 binds LPS and restrains high
fat/lard-induced liver injury and fat storage 335. For further context, in other postprandial trials
cream-induced liver fat was attenuated by co-administration of 50g glucose but
not fructose 336, which itself
may also be capable of inducing endotoxemia 337, DNL and ceramides 338.
This unique effect of glucose may involve its ability to stimulate insulin and thereby
inhibit adipose lipolysis and fatty acid flux to the liver 336. Similarly, in humans experimental
endotoxemia induces peripheral inflammation, oxidative stress and lipolysis, the
latter 2 of which were particularly inhibited by co-infusion of insulin 339. Such endotoxemia also induces ceramides
in VLDL and LDL 340, which in
rodents is accompanied by activation of S-SMase in serum and de novo sphingolipid biosynthesis (i.e.
SPT) in liver 340,341. Therefore
LPS may mediate some of the differential immuno-metabolic effects of SFAs herein.
Microdomains
The body is an aqueous environment and lipids are stored and
transported in amphipathic membranes which exhibit heterogeneous biophysical
properties in relation to their specific compositions. The plasma membrane exists
largely in a state of liquid-disorder (Ld) with distinct liquid-order
(Lo) microdomains (aka. lipid rafts) which are characteristically
detergent-resistant and enriched in cholesterol and saturated sphingolipids 342. Such rafts may serve as functional
platforms to assemble proteins subserving cell signalling and endocytosis 343, which can be modulated by exogenous lipids.
In particular, free cholesterol in the lipoprotein monolayer is in equilibrium
exchange with cell membranes 344,
while VLDL and LDL were reported to preferentially interact with model membrane
raft regions, consistent with the high affinity of apoB100 for
cholesterol (and contrasting triglyceride-rich chylomicrons) 345. Further, the hepatic LDLR is
associated with both clathrin and caveolae-rich membrane regions 346 (which correspond to non-raft and
raft regions, respectively 343),
and treatment with LDL or cholesterol induced translocation to caveolae
coinciding with reduced LDL uptake 346.
In non-hepatic cells 44 internalised
LDL-c also travels from lysosomes to plasma membrane first before ER regulatory
domains 347. And in the other
direction, the ABCA1 transporter may associate with cholesterol-rich lipid
rafts 348 to mediate efflux to
apoA-I/HDL 349; indeed the
composition of nascent HDL resembles lipid rafts 349. Therefore conditions of high membrane cholesterol may
favour reduced uptake and increased efflux. Membrane fluidity is also
determined by lipid saturation, with Ld regions containing phospholipids
enriched in UFAs. Challenging cells with PUFAs results in rapid plasma membrane
incorporation and compensatory induction of saturated lipids and cholesterol to
maintain biophysical homeostasis 350.
Conversely, exogenous SFAs induced accumulation of saturated glycerolipids in
the ER and solid phase (i.e. solid-order, So) membrane separation in
a manner correlating SFA chain length and offset by UFAs 351. In monkeys corn oil/n-6 PUFAs (vs.
coconut oil/SFAs) increased LDL uptake by PBMCs which correlated membrane
fluidity and lower plasma cholesterol 352;
while in vitro enrichment of hepatocytes
in various fatty acids affected LDL binding/metabolism and membrane fluidity in
a highly correlated manner (i.e. n-6 PUFAs > MUFAs > SFAs), without
altering total or esterified cholesterol 353.
Fatty acid fluidity might also affect lipoprotein packing and surface protein
conformation 146, as well as lipid
droplet hydrolysis and cholesterol efflux 103,251,354.
Lipid microdomains are directly implicated in vascular
function and atherogenesis. Firstly, LDL induces transcytosis of macromolecules
through endothelium via the LDLR, cholesterol and caveolae 125. In human atherosclerotic plaques the
oxLDL receptor LOX-1 is also associated with caveolae and dissociated by statins
or MβCD (which extracts
membrane cholesterol), thereby abrogating oxLDL-induced apoptosis 355. As above, LDL can also deliver ceramide
to endothelial cells 209,
where endogenous ceramide promotes the uptake and retention of oxLDL via regulation
of transcytosis-related and raft-associated proteins, including LOX-1 211. Further, hypercholesterolemia and
LDL inhibit endothelial nitric oxide synthase (eNOS) via translocation to
caveolae rafts (reviewed in 61).
Hypercholesterolemia and 7-ketocholesterol also induce endothelial A-SMase/ceramide-dependent
membrane raft redox signalling platforms linked to NLRP3 activation 356. Notably, electronegative LDL also possesses
intrinsic SMase activity associated with apoB100 serine O-glycosylation 357; this may be outward-facing so as to
engage plasma membrane sphingomyelin, generating ceramide-based microdomains
and endocytic vesicles 358,359.
Moreover, arterial SMase can hydrolyse sphingomyelin within lipoproteins
themselves generating ceramide-rich domains, which may act as nonpolar spots
promoting aggregation via hydrophobic interaction 57, as well as displacement and release of cholesterol to
neighbouring vesicles 360. Atherosclerotic
plaques were also reported to contain membranes enriched in free cholesterol
and crystalline domains 61. In
preclinical studies plaque crystals co-associated with cholesterol microdomains
361, which can be shed from
macrophage membranes 362.
Rapid loading of macrophages via phagocytosis of large lipid droplets induces
lysosomal free cholesterol and extracellular crystals 50; inhibition of esterification also
induces crystals and cytotoxicity offset by extracellular acceptors (i.e. apoA-I/E)
mediating efflux of cholesterol from the plasma membrane 363,364. Further, lipid oxidation induces
crystalline domains in model membranes under conditions of hyperglycaemia,
which can be inhibited by n-3 PUFAs (esp. EPA) 365. More specifically, smooth muscle cells grown in the
presence of 7-ketocholesterol produced extracellular crystals via formation of distinct
membrane microdomains due to reduced intercalation with phospholipids 366.
Regarding immuno-pathogenesis, in human cohorts LDL-c
correlated a haematopoietic monocyte skewing (vs. granulocytes) in blood 367 and proinflammatory macrophage
phenotype in adipose 368, which
were suppressed by statins. One potential pathway involves CD131, the common β subunit of GM-CSF and IL-3
receptors. Accordingly, in LDLR–/–
mice administration of lipid-free apoA-I reduced aortic cholesterol and
macrophage deposition, as well as systemic CD131+ immune cells and their
CE content, while in vitro LDL and
apoA-I oppositely regulated monocyte membrane cholesterol shifting CD131 between
raft and non-raft fractions, respectively 369.
In addition, in an RCT on obese individuals, dual lipid-lowering therapy for 6
weeks markedly lowered apoB and lipids (e.g. LDL-c 141–73mg/dl), as well as
fasting and cream/SFA-induced LPS and immune cell activation; postprandial PBMC
TLR2/4 expression was even below baseline (i.e. Fig. 3G/H) 322. Of relevance here, in LPS-stimulated
macrophages TLR4 activation requires cholesterol biosynthesis (via FASN) to
enter lipid rafts 370, while ABCA1-dependent
cholesterol efflux suppresses raft-associated TLR/inflammatory signalling in
macrophages 371,372 and
endothelial cells 373.
Shortly after the discovery of TLR4 as the LPS receptor it
became apparent that fatty acids could also modulate TLR signalling 374. In particular, at higher levels than
bacterial ligands, free SFAs can also induce TLR4 and 2 signalling (esp. lauric
and palmitic acid) via NOX/ROS and cholesterol-dependant rafts 375,376, and potentiate that by TLR
ligands, all of which is inhibited by UFAs (esp. DHA) 374,377. Paralleling this, bacterial LPS
and lipopeptides are acylated with chains of SFAs which are required for TLR4
and TLR2 signalling, respectively. For instance, in E. coli LPS the lipid A region is typically hexa-acylated with
C14/12 SFAs 378, while
hypo-acylation or incorporation of UFAs result in antagonist activity 374,377; similarly, total gut LPS
silences TLR signalling due to hypo-acylated lipid A in Bacteroidales 274.
Cellular sensitivity to low levels of LPS is supported by initial binding to surface
CD14/CD36, which facilitates transfer to the TLR4–MD2 complex 379, wherein its saturated acyl chains interact
with MD2 lipid domains inducing TLR4 dimerization 377. As a corollary, free fatty acids (SFAs and UFAs) may also
bind within the hydrophobic pocket of MD2 to directly modulate TLR4 signalling 377,380,381, while other evidence suggests
palmitate acts indirectly via lipid metabolism and ER stress 382. As above, lowering the dietary
palmitate/oleate ratio can lower PBMC LPS sensitivity, while principle
component analysis implicated corresponding changes to tissue lipids in the
mechanistic pathway 326. In
line with this, in hyperlipidemic mice systemic inhibition of the ER-associated
enzyme SCD1, which mediates endogenous desaturation of SFAs to MUFAs, induced macrophage
TLR4 hypersensitivity 383. Since
plasma membrane rafts are rich in polar lipids with saturated acyl chains and
can be modulated by SCD1 383
and n-3 PUFAs 377, this may
contribute to general effects. LPS and oxidative stress-induced raft–TLR4
complex formation also requires A-SMase-derived ceramide 384,385 (which has structural
similarities to lipid A 386),
while palmitate augments LPS inflammatory responses via SMase and de novo ceramide synthesis 387–390. Free SFAs (i.e. palmitic and
stearic acid) can also activate macrophage NLRP3 inflammasomes via flux into
phosphatidylcholine and ER stress 391,
and even crystallisation 392,
which are offset by UFAs. Consequently, SFAs may stimulate and sensitise innate
immune signalling in various ways and have been suggested to mediate
LPS-associated postprandial inflammation 393.
Lipid rafts are also involved in endocytosis 343 and represent a common entry point
for many viral, bacterial and fungal pathogens 394–396. For instance, in the colon butyrate may inhibit
enteric pathogen invasion via depletion of cholesterol and increased membrane
fluidity 397. Similarly, in
porcine ileum samples SFA-induced LPS permeability was abrogated by MβCD, implicating lipid rafts 319. Another study using oleate and
taurocholate (which is especially induced by SFAs 315) further implicated a raft/CD36-dependent pathway 334. Of additional interest, intestinal
enterocytes were reported to phagocytose E.
coli/LPS via TLR4, while in mice TLR4 deficiency prevented bacterial
translocation in response to injury 398,
and induction of faecal/plasma LPS by a high fat/lard diet 399. The differential effects of fatty
acids on TLR4 signalling 374
also parallels those on postprandial LPS 319.
Ecology
Evidence of atherosclerosis has been reported in ancient
humans spanning 4000 years and from diverse locations suggesting a basic
predisposition 400; patterns
of systemic vascular calcification were even similar between ancient and modern
Egyptians, appearing in aorta–iliac beds almost a decade prior to event-related
coronary and carotid beds 35. These
populations may have been exposed to various enduring risk factors, including
diet, smoke and infections, although this remains speculative 401. However, there are some notable
examples of extant pre-industrial people with divergent health outcomes,
suggesting post-industrial changes are also important 402. Foremost, the Tsimane
forager-farmers of Bolivia are a tropical subsistence population with a high
infectious/inflammatory burden, yet some of the lowest ever reported coronary
artery calcium (CAC) scores throughout life 403; as well as atrial fibrillation 404, age-related brain atrophy 405 and dementia 406.
Lipids likely play a fundamental role in our susceptibility
to CVD. Indeed many other mammals are relatively resistant to atherosclerosis
and exhibit low apoB-lipoproteins so their use as experimental models requires induction
of hyperlipidemia via manipulation of genes and/or diet 69,103,407; although important metabolic differences
remain (e.g. LDLR/APOE knockout 407,
no CETP 69, ACAT2 expression 42,117 and LCAT specificity 138,139). Further, unlike small animals, in
human arteries plaque-prone regions
exhibit diffuse intimal thickening, which is initiated in utero 40,56.
Presumably these adaptations augment vessel strength and elasticity in response
to mechanical stress, while also seeding the soil for atherogenesis 40,48,56. Under physiological
conditions endothelial transcytosis of lipoproteins may also support vascular lipid
metabolism and immunity 54,121,
but since cholesterol is not catabolised here this creates a vulnerability to
accumulation under hypercholesterolemic conditions. In particular, endothelial 128 and smooth muscle cells 408 treated with native or aggregated
LDL, respectively, seem to have a limited capacity for efflux compared to
myeloid cells, and during atherogenesis may be an early site of crystallisation,
driving inflammation 62,128. Moreover,
experimental atherosclerosis requires NLRP3 130, suggesting a lipid–immune vicious cycle and implicating
other cell stressors. Foremost,
many infections are associated with atherosclerosis and the acute-phase
response induces metabolic changes implicated in CVD, which may support
immunometabolism, signalling and defence 409,410.
For instance, infections/inflammation modulate systemic insulin sensitivity
(i.e. glucose metabolism) 411,412,
lipid metabolism (e.g. lipolysis, cholesterol and sphingolipids) and
lipoprotein modifications (e.g. oxLDL) 410.
More specifically, macrophages switch to a glycolytic metabolism and accumulate
lipid droplets with antimicrobial activity 413,
which depend on CD36 (i.e. lipid import) 414.
Further, LPS–TLR4 signalling requires cholesterol
synthesis 370 and inhibits
systemic reverse cholesterol transport 309, while various
inflammatory mediators induce LDL transcytosis through endothelium 131, which may further increase lipid availability. Bacterial
sequestration may be supported by vascular retention (e.g. LPS–TLR4 275,306 and M. tuberculosis 49)
and phagocyte clearance by LDL binding (e.g. LPS 307,308 and group A Streptococcus
415). These mechanisms could therefore
support acute survival, while persistent stimulation exacerbates vascular disease
hastening late-life mortality 410,
as a form of antagonistic pleiotropy. Indeed while CVD is currently the leading
cause of death, ancestrally it was likely infections and injury 402, underscoring the evolutionary
priority.
Many bacterial pathogens are Gram-negative with a distinct outer
membrane coated in LPS, which confers barrier function and protection from
antibiotics 416. The specific composition
of LPS varies between bacteria and is modulated by environmental factors 416. In pathogenic bacteria the lipid A
region is typically hexa-acylated with SFAs 378, which may impart a gel-like state and low permeability,
while also mediating activation of innate immunity in mammalian cells via Lo
microdomains, which are similarly enriched in SFAs 417. As above, SFA-rich diets may act on gut and liver to increase
circulating immunogenic lipids (e.g. cholesterol, ceramides and LPS) which
converge on membrane microdomains. Further, in healthy adults SFA intake and SCD
(aka. ∆9-desaturase) activity
also correlated the kynurenine/tryptophan ratio (a surrogate of IFNg/Th1
activity), which itself correlated CRP 418.
In mice SFA-rich diets (i.e. C12/16:0) exacerbated central autoimmunity by
increasing Th1/17 activity via the small intestine 419,420. Th17 cells express particularly high levels of TLR4,
and LPS directly induces Th17 differentiation in vitro 421.
Accordingly, Th17 lymphocytes are part of type-3 immunity which mediates
antimicrobial responses to extracellular pathogens (e.g. Gram-negative
bacteria), although when dysregulated also autoimmunity 422. In addition, in Rag1–/– mice lacking adaptive immunity, a SFA-based
ketogenic formula enhanced clearance of C.
albicans, while simultaneously conferring susceptibility to endotoxemia,
which involved palmitate and ceramide, persisted for 7 days post-exposure, and
was reversible with oleate 423.
This was consistent with SFA induction of innate immune memory (i.e. ‘trained
immunity’), itself another double-edged sword 424. As above, plasma cholesterol may similarly stimulate
immune cells, and while treatment of human hypercholesterolemia with statins
normalised monocyte skewing and lipid droplets, an activated phenotype
persisted, again implicating trained immunity 367. Dietary cholesterol may also affect the pathophysiology
of infectious and autoimmune disease (reviewed in 425).
The ability of exogenous lipids to differentially regulate endogenous
lipids and physiology may arise from several key factors. Foremost, the
dependence of membrane biophysics and cell signalling on specific fatty acids
means lipid saturation must be tightly regulated; indeed excess long-chain SFAs
can induce cell stress/inflammasome pathways, which are offset by UFAs 392 via increased membrane unsaturation 351,391 and SFA channelling into triglycerides
and β-oxidation 426,427. Similarly, the ER-associated enzyme
SCD mediates endogenous desaturation and protects from SFA toxicity in various
cell types; and in human adipocytes DNL and SCD were functionally coupled,
which may underlie the lipogenic effect of SFAs 428. Accordingly, postprandial TRL fatty acids may induce
foamy monocytes via ER-derived lipid droplets with increased unsaturation to
protect from SFA toxicity 175.
This lipogenic cost is also illustrated in hyperlipidemic mice on SFA or
MUFA-rich diets where deficiency of SCD suppressed obesity-related metabolic
disorders and triglycerides, while inducing atherosclerosis, plasma SFAs and macrophage
TLR4 hypersensitivity 383. Furthermore,
despite SCD, the dietary SFA/MUFA ratio still modulates tissue ratios (and
physiology) 200,326 and we are
especially limited at de novo PUFA
synthesis, underlying the essential fatty acids (i.e. C18:2/3). Similar issues pertain to cholesterol, which
is also fundamental to membrane physiology, but in excess can precipitate as
crystals and exert toxicity. While most cells can synthesise cholesterol its
catabolism is limited in extrahepatic tissues to side chain oxidation (via
sterol 27/24-hydroxylases) and steroidogenesis (in hormonal glands), with ultimate
conversion to bile acids occurring in the liver. Therefore excess cholesterol must
be esterified for storage or effluxed (via HDL, RBCs or albumin 246,429) for transport to the liver and
intestine for biliary and direct excretion, respectively. Fatty acid and cholesterol
metabolism directly converge on the formation of cholesteryl esters, which have
a preference for UFAs (i.e. ACAT 116,136
and LCAT 140–142), suggesting their availability may
influence cholesterol turnover and therein processes of uptake/efflux,
transport and crystallisation; interspecies differences in LCAT specificity for
PUFAs may also correlate susceptibility to (diet-induced) atherosclerosis 139. Differential modulation of gene expression
may affect systemic metabolism and sterol excretion 95,135, while in the gut modulation of microbial
cholesterol 158 and bile acid metabolism
315 may also be important. Further, the role
of lipids and lipoproteins in immunity may superimpose another layer of
regulation 410.
Consequently, these metabolic constraints and connections
create a susceptibility to different foods and associated environments, which themselves
may confer adaptive or maladaptive effects on short-term fitness or long-term
health, in concert with genomic variation. How might this play out through our evolution?
The other great apes from which we diverged are highly plant-based (e.g. total
fat ~14–17% kcals; PUFA/SFA ratio ~0.9–1.7) 430,431, after which our diet became
increasingly diverse and animal-based with our spread to colder environments
and pastoralism 432. Initially
the hepatic LDL shunt pathway may have evolved to favour cholesterol
conservation 44, while an increase
in dietary cholesterol and fats from animals (i.e. land and marine) and plants
(esp. nuts/seeds) may have further modulated plasma cholesterol in relation to
the PUFA/SFA ratio 92,93,97,116,134.
In parallel, the susceptibility of meat to deterioration might have also
increased exposure to pathogens, consistent with our relatively low stomach
acid pH (i.e. similar to scavengers) 432
and animal food aversion during early pregnancy (i.e. morning sickness), a
relatively immune-suppressed period 433,434.
The advent of cooking would support sterilisation and may be reinforced by the
appealing sensory qualities of advanced glycation end products (AGEs) 435, albeit at the potential cost of cardiometabolic
dysregulation, as seen in modern humans 436.
However, despite these physiological challenges native populations often
exhibit relative cardiometabolic health 402,437.
For instance, our genus and species emerged in Africa, where remaining
hunter-gatherer exemplars such as the Hadza of Northern Tanzania maintain low
body weight, blood pressure and plasma lipids throughout life 402, with a low fat intake (i.e. median ~18%
kcals) from plants and lean meats 432.
Similarly, Tsimane vascular health is accompanied by a low LDL-c (esp. till
2011) 403 and fat/SFA intake
(i.e. men: 15.1/3.7% kcals, respectively) from a plant-dominant diet with
moderate fish/meat 438. Furthermore,
in this energy-limited and pathogenically diverse context, the ancestral APOE4 allele is actually associated with
better cognition in those infected with parasites 439, and slightly increased lipids (i.e. cholesterol +2.8%
and oxLDL +3.9%) and lower innate immune markers (e.g. CRP –21.6%), which were
inversely associated in those with a lower BMI only 440, suggesting it may not have the same
deleterious effects as in post-industrial populations, but instead support
cognition and immunity.
Like many isolated native populations the Tsimane are now in
a state of nutritional transition as they increasingly interface market towns, with
corresponding changes to cardiometabolic health of increasing body fat 438 and plasma lipids 403 (see Table S6). Earlier clinical
studies on the Tarahumara Indians of Mexico showed their similarly low plasma
cholesterol increases rapidly in response to dietary cholesterol 441 and an ‘affluent’ diet 442. In industrialised societies major
SFA sources are now grain-fed meats (which are richer in fat and lower in n-3
PUFAs than grass-fed 443) and concentrated/added
fats from animals/dairy and tropical plants (as used in SFA trials herein), in
the context of a diet high in ultra-processed foods/calories and low in micro-/phytonutrients,
implicating evolutionary mismatch in SFA-associated diseases 437. Indeed many nutritional and
physiological factors may modulate the effects of dietary SFAs today (and serve
as study confounders). For instance, SFA-induced elevations in plasma cholesterol
may depend upon intake of dietary cholesterol 92,93, plant-based PUFAs 116,134
and associated phytosterols 155,156.
SFA-induced postprandial inflammation may especially occur in obesity 322,323,444, but be blunted by lipid-lowering
therapy 322 or co-ingestion of
phytochemicals (e.g. polyphenols 445,
spices 446 and fibre 447), which can also accompany UFAs (e.g.
olive oil and nuts). Of UFAs, cellular levels of long-chain (marine) n-3 PUFAs are
particularly responsive to diet and exhibit robust anti-LPS/TLR effects 315,318,319,374,377 (not without
potential for excess 448,449),
implicating omega-3 status. SFA-induced liver fat may be promoted by poor
metabolic health 450, overfeeding
185,187–189 and excess
fructose 336. Conversely, low
carbohydrate diets may mitigate the differential effects of SFAs (vs. UFAs) on
insulin sensitivity and inflammation, but not cholesterol, SCD and ketones 86–90. Accordingly, low carbohydrate
diets increase muscle fat oxidation 86,
which can protect muscle cells from palmitate toxicity in vitro 426; ketosis
also has inherent anti-inflammatory effects 451 and a 3-day isocaloric ketogenic diet suppressed
LPS/palmitate-induced NLRP3 inflammasome activation in macrophages in vitro 452.
Also noteworthy,
over the past century consumption of seed oils/n-6 PUFAs has greatly increased
and beyond what may be possible in pre-industrial diets 29,
but with a corresponding enrichment of blood/adipose associated with favourable
CVD and cancer outcomes 453, seemingly
creating an ecological disconnect. In the contemporary context however, such benefits
are realised when dietary n-6 PUFAs/linoleate replace “carbohydrates” or SFAs/dairy
fat 3,5,13, which are also typically
refined/concentrated from wholefood and evidently more maladaptive. In this
regard, seeds feature in native 432
and ancient diets 454, with some
tree nuts also being rich in n-6/n-3 PUFAs (e.g. walnuts, mongongo and pine
nuts); and other primates consume a high proportion of PUFAs from fruit (>n-6)
and leaves (>n-3) 430,431. Nonetheless
several trials herein of n-6 PUFAs (vs. SFAs) in humans 95 and mice 104–106 do show some tissue-specific signs of inflammation. Of potential
relevance, recent human studies suggest dietary linoleate may have opposite
effects on serum CRP and adipose inflammatory gene expression in relation to FADS1 genotype 455. Linoleate intake can also affect
peripheral long-chain n-3 status 456
and supplemental EPA bioavailability (vs. SFAs) 457, presumably via competition for biosynthetic and
esterifying enzymes; although in reciprocal long-chain n-3 intake can lower long-chain
n-6 458, suggesting the importance of balance. From
a natural wholefood context, plants (esp. nuts/seeds) can be rich in
C18-MUFAs/PUFAs (n-6 and n-3, as above) and marine life long-chain n-3 PUFAs,
while terrestrial animals lean, broadly consistent with current health
associations in post-industrial people.
Overall, while many factors may promote atherogenesis, as a
condition of arterial lipid accumulation, a lipid-threshold may ultimately
govern its progression 459,460.
Accordingly, atherosclerosis infrequently occurs in mammals and humans with an
LDL-c <80mg/dl 49,344; including
the Tsimane (with chronic inflammation) 403
and the middle-aged PESA cohort (without conventional risk factors) 34. Moreover, decades of research on
experimental atherosclerosis shows that most aspects of advanced plaques can
regress/reverse, including necrotic and crystalline material, in association
with dramatic lipid lowering and improved HDL function 129,461,462. Similarly, in humans athero-regression
can be induced with intensive lifestyle changes 463 (with <SFAs 84,203)
and/or lipid-lowering drugs 464
(with LDL-c <80mg/dl 465,466);
and some extreme cases have been reported 467,468.
In fact when considering other mammals, newborn humans and native populations,
these low cholesterol levels may even be physiologically normal 344,469; in which case athero-regression could
simply reflect a return to the natural homeostatic state. So despite its
ubiquity, perhaps atherosclerotic CVD is not inevitable, at least not without
chronic deviation from physiological homeostasis as a result of unfavourable
gene–environment interactions. In this regard, dietary fat quality may be
important via effects on plasma lipids and the immuno-metabolic milieu (Box).
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