Solid vs. liquid fat—a biophysical perspective

As reviewed previously, dietary fats have differential effects on the body in relation to various mechanisms. This post explores why from a more fundamental perspective.

The body is largely an aqueous environment, compartmentalised by amphipathic lipid barriers/membranes containing specific hydrophobic fatty acids; and similarly, lipids are transported in amphipathic lipoproteins and metabolised by water-soluble enzymes (e.g. lipases). However, dietary fats have diverse structures and physiochemical properties. Foremost, unsaturated fatty acids (UFAs) are liquid at body temperature (37°C), while saturated fatty acids (SFAs) have higher melting points, which increase with chain length, resulting in short–medium chain fatty acids (e.g. C3–11:0) being liquid and longer chains solid; with a parallel relationship to water insolubility (Wiki). Could these basic characteristics underlie some of their differential effects?

Differential metabolism

Most well-known is the ability of dietary fats to modulate blood lipids. In particular, saturated fats increase cholesterol (esp. total/LDL ¹; even eucaloric low-carb ^2,3); the extent of which is related to apoE genotype ^4–6. This effect is mainly attributed to the more prevalent C12–16:0 SFAs (relative potency: C14>16>12) ^7,8, while stearic acid (C18:0) is considered neutral ⁹. However, some less prevalent SFAs may also elevate cholesterol ^10–12; for instance, medium-chain fats (i.e. C8:0/10:0) ¹³ and behenic acid (C22:0) ⁸ had lower and greater potency than C16:0, respectively, and both increased endogenous C12–18:0 SFAs, suggesting indirect effects ^8,13. Replacement of SFAs with UFAs lowers cholesterol, but PUFAs/C18:2 more so than MUFAs/C18:1 ^1,7,14; and of PUFAs, linoleic acid (C18:2, n-6) and α-linolenic acid (C18:3, n-3) may be similar ^15,16. Whereas supplementing long-chain omega-3 (typically fish oil) may have no effect ¹⁷, or increase cholesterol in relation to oil oxidation ¹⁸, DHA (C22:6, n-3) ^19–21 and apoE genotype ¹⁹. Fat modulation of blood lipids extends to lipoprotein turnover; for instance, diets rich in typical SFAs decrease the LDL fractional catabolic rate (FCR) and LDL receptor (LDLR) expression/activity ^12,22–25 (even postprandially ²⁶), and therefore tissue uptake; also affected by apoE genotype ^4,19. But why would fats differentially affect lipoprotein metabolism?

Fundamentally, fats are the most calorie-dense macronutrient, and can essentially be oxidised immediately for energy, or stored as esters in more complex lipids (e.g. phospholipids, triglycerides and cholesteryl esters) and used in other functions (e.g. signalling and membranes). Different fatty acids have different metabolic fates (reviews ^27,28). For instance, in human tracer studies, whole-body oxidation of specific fats decreases with chain length (e.g. C12:0>16:0>18:0 ²⁹ and C18:3>22:6 ³⁰) and saturation (e.g. C16:0/18:0 vs. C18:1/18:2/18:3; Fig. 4) ^9,29,31. Short-term trials also show overfeeding with SFAs (vs. UFAs) specifically induces greater liver fat ^32–34, while low carb diets favouring UFAs (vs. SFAs) induce higher blood ketones (e.g. after 5 days ³⁵ or 6 weeks ^2,3). Tissue studies further highlight differential and interactive effects (e.g. intestine ³⁶, hepatocytes ^37,38 and myotubes ^39–42). For instance, in myotubes, medium-chain fats (i.e. C10:0/12:0 vs. C16:0/18:1/18:2) induced the highest mitochondrial oxidative capacity and lowest ROS and lipid accumulation ⁴³; while palmitate (C16:0) generally had higher oxidation and esterification than oleate (C18:1), which increased with co-administration of UFAs (i.e. C16:0 + C18:1 or 20:5) ^39–42. In hepatocytes, stearate (i.e. C18:0 vs. C16:0/18:0/18:1/18:2) had particularly low oxidation and incorporation into various lipids ²⁸, remaining relatively unmetabolised ^37,38. Coincidently, oxidation of long-chain fats may induce ROS via LCAD (esp. in liver), where stearate had the fastest H₂O₂ production kinetics ⁴⁴. Long-chain UFAs (vs. SFAs) may also have greater liver metabolism to ketones ^24,30,37,45; a suggested mechanism by which PUFAs may lower production of triglycerides and VLDL/LDL-c ⁴⁵. Note however, medium-chain C8–12 SFAs have high oxidation rates yet can elevate blood triglycerides and cholesterol (vs. UFAs) ^11–13; replacing long-chain SFAs with UFAs may have no effect on triglycerides, unlike cholesterol ⁴⁶; whereas supplementing long-chain omega-3s can dose-dependently lower blood triglycerides, by lowering VLDL production and increasing fatty acid uptake/oxidation ^19,47, with discordant effects on cholesterol, as above.

However, the first stage of metabolism is digestion. Notably, in the human tracer studies above, SFAs were dissolved in liquids which facilitate absorption, while oxidation was far lower with capsules ²⁹. Accordingly, digestion of (long-chain) fats initially involves emulsification by bile acids, forming micelles which increase surface area and facilitate hydrolysis by pancreatic lipase. Diets high in SFAs especially seem to favour secretion of taurine-conjugated bile acid (i.e. taurocholate) ⁴⁸, and related outgrowth of sulphite-reducing bacteria ^48–51, which are inhibited by omega-3s ^52–54; while taurine supplementation can particularly enhance absorption of SFAs, in relation to their chain length and hydrophobicity ^55,56. Moreover, in animal models, even micellar palmitic acid (the most common dietary SFA) has a relatively slow absorption (vs. UFAs), requiring more length of intestine and taurocholate ^57–59. This was linked to differential metabolism by intestinal enterocytes, where palmitic vs. linoleic acid was more slowly re-esterified to triglyceride (esp. with lower taurocholate) ⁵⁸. Further, while the intestine mainly secretes triglycerides via chylomicrons into lymph, palmitate also induced some smaller VLDL-like particles (i.e. lower triglyceride/protein ratio) ^36,60. Subsequently, similar differential effects were reported on hepatic VLDL secretion (e.g. palmitic vs. oleic ⁶¹ or palmitoleic acids ⁶²).

Interestingly, while diet can alter blood fatty acids ^{2,3,8,13,14,63–68}, there is still a predominance of SFAs (esp. C16:0), MUFAs (esp. C18:1) and PUFAs (esp. C18:2), in plasma phospholipids, triglycerides and cholesteryl esters, respectively; even with ~60% fat diets favouring SFAs or UFAs ³. This suggests esterification is highly regulated and may be limited by fatty acid availability (e.g. FFA/albumin ratios) ³⁸. Accordingly, in cells, palmitate accumulates in phospholipids, glycerides and ceramides, while oleate and EPA support channelling into triglycerides (and β-oxidation), via regulation of DGAT2 ^40–42, which meditates the final step of triglyceride synthesis (i.e. DAG–TAG). UFAs also favour cholesterol esterification by ACAT, while SFAs (C12–16:0) suppress esterification and increase free cholesterol (in the ER), which may inhibit hepatic LDLR expression ⁶⁹ and VLDL-c secretion ⁷⁰. Note, the blood cholesterol-lowering ability of common fatty acids parallels their cholesteryl ester content (i.e. C18:2>18:1>16:0) ^3,14,68; while stearate may lower liver cholesterol and increase faecal excretion ^71,72, by lowering secondary bile acids and cholesterol solubility/absorption ^73–75. Moreover, dietary fats also have differential effects on lipogenesis. While eucaloric low-carb diets favouring SFAs or PUFAs can lower lipogenesis ², diets favouring MUFAs and PUFAs specifically lower desaturation (i.e. SCD activity) ^2,65,68,76, and high dietary SFAs or PUFAs can upregulate desaturation ^77–79 or saturation ⁷⁶, respectively (alongside cholesterol ^76–78). Thus cells regulate their fatty acid balances (e.g. via differential regulation of SCD-1 ^78–81, PGC-1β ^77,78 and SREBPs ^22,76,82,83), which may maintain preferred substrates for esterification. Accordingly, DGAT2 co-localises with SCD-1 (in the ER) ⁸⁴, which mediates production of the major MUFAs (C16:1 and 18:1), and supports their esterification ^85,86. Also, blood SCD indices correlated triglycerides, but negatively with several PUFAs (LA and EPA/DHA) ^87,88, which can suppress SCD-1/SREBP-1c expression in hepatocytes ⁸⁸ and macrophages ^81,89. Therefore, the storage and utilisation of dietary fats may involve counter-regulation of lipid saturation; but what principles underlie the bodies preference for specific fatty acid profiles?

Differential biophysics

A major fate of fats is incorporation into membranes, which compartmentalise cells and regulate biomolecule transport and signalling. Cell membranes are heterogeneous, containing hundreds of lipid species associated with distinct biophysical phases, such as liquid disorder (Ld) and liquid order (Lo), which may support specific processes ^90,91. Fundamentally, membrane amphipathicity is mediated by polar lipids (e.g. phospholipids and sphingolipids), which typically consist of a hydrophilic head attached to a hydrophobic tail (acyl chain) of fatty acids, which determine physiochemical properties, lipid–sterol interactions and membrane biophysics (e.g. fluidity/viscosity, elasticity/compressibility, permeability, fusion, flip-flop, etc.) ^92–94. For instance, SFAs are straight molecules which confer order and rigidity, while the double-bonds of UFAs introduce disorder and flexibility. An extreme example is DHA (C22:6, n-3), which contains many double-bonds and confers a loosely packed and dynamic membrane, with high fluidity, compressibility and permeability ⁹². Generally, plasma membrane bilayers are asymmetric; the inner leaflet possessing greater phospholipid unsaturation and fluidity, and outer leaflet being particularly rich in saturated sphingolipids, which can support Lo nanodomains termed ‘lipid rafts’ ⁹¹. However, membrane composition varies by organelle and cell/tissue, likely reflecting specific biophysical requirements; e.g. DHA being especially high in brain, retina and sperm.

While dietary fats vary widely in quantity/quality, plasma and organ phospholipid (i.e. membrane) fatty acid composition is highly regulated across different diets ⁹⁵; although is susceptible (e.g. human muscle ^65–67), and especially to PUFAs, given their limited biosynthesis ⁹⁵. Such regulation involves crosstalk between membranes and metabolism, as exemplified by homeoviscous adaptation ^76,96. For instance, exogenous PUFAs can be rapidly incorporated into membranes, and at high doses, upregulate SFA and cholesterol synthesis to maintain biophysical properties and fitness ⁷⁶. Accordingly, cholesterol preferentially interacts with saturated lipids and supports Lo phase ^90,92,97, while membrane fluidity is linked to cholesterol biosynthesis via HMG-CoA reductase ^98–102. As above, SFA loading can induce lipogenesis and SCD/desaturation to produce MUFAs ^78–80, which may support their oxidation and storage (as triglyceride vs. DAG/ceramide), and maintain cell physiology (e.g. membrane fluidity and insulin sensitivity) ^40,41,80. In particular, plasma membrane raft regions are especially rich in cholesterol and saturated sphingolipids ⁹⁰; where exogenous saturated and omega-3 fats oppositely regulated raft-dependant TLR signalling ¹⁰³ and intestinal permeability ¹⁰⁴; and omega-3s enriched tight junction microdomains preventing disruption by inflammation ^105,106. Further, inside cells, metabolism of SFAs can even induce solid phase separation in ER membrane (and eventually cell death), in relation to the chain length (e.g. C12<14<16<18) and phase transition temperature (T_m) of their metabolites, which was offset by UFAs (i.e. C18:1/22:6) ¹⁰⁷. Note, compared to plasma membrane, the ER is cholesterol-poor, while cholesterol eliminates solid phase behaviour ¹⁰⁷. On the other hand, excess free cholesterol can cause membrane/organelle dysfunction and precipitate into crystals, triggering inflammasome activation ^108,109. Similarly, free SFAs were also reported to induce crystallisation and inflammation in macrophages, which was inhibited by UFAs (i.e. C18:1/18:2/18:3), alongside accumulation of triglycerides ^110,111. Taken together, these studies link cellular SFA/UFA balances to lipid biophysics, attesting the importance of (and rationale for) their tight regulation.

Similar principles may apply during (neutral) lipid storage and transport. As above, excess free fatty acids (FFAs) and free cholesterol (FC) are cytotoxic, but can be esterified and encapsulated within a phospholipid monolayer for intracellular storage in lipid droplets or intercellular transport in lipoproteins, the composition of which affects biophysical properties. In particular, cholesteryl esters can exist in liquid–crystalline states dependant on acyl chain length and unsaturation ^112–114; where esterification with C18:2/PUFA may support fluidity ^114–117, as may the presence of MUFA-based triglyceride (i.e. triolein) ^117–120. As discussed earlier, SFAs can induce secretion of denser VLDL particles, with a lower triglyceride/cholesterol ratio ^58,60–62; suggested to result from slower triglyceride esterification ⁵⁸ and compensate insolubility ⁶¹. Higher fat and saturated fat diets (incl. SFAs vs. MUFAs ¹²¹) may also particularly increase large-buoyant LDL ^122,123 (i.e. rich in PL/CE/FC, not TGs ^124,125). Note, conditions of lower triglyceride availability are thought to promote formation of large LDL, while elevated levels favour small-dense LDL ^122,126. Diets favouring n-6 PUFAs over SFAs can lower many VLDL–LDL particle sizes and lipids ^24,127; as may high-quality vs. oxidised fish oil ¹⁸. This may involve modulation of lipoprotein turnover ^22,23, in association with biophysics. For instance, high-PUFA diets have increased LDL PUFA content, alongside LDL fluidity ¹²⁸ and LDLR binding ⁶⁴; and similarly, in vitro, linoleate most increased hepatocyte membrane fluidity and LDL uptake (i.e. C18:2>18:1>Ctrl>18:0/16:0), which were highly correlated ¹²⁹. In addition, LDL aggregation potential was related to surface sphingolipid content, and lowered by a ‘Healthy Nordic diet’ (incl. higher PUFA/SFA ratio) or lipid-lowering therapy ¹³⁰, whereas overfeeding saturated fat had the opposite effect ¹³¹.

Lipid saturation also determines redox sensitivity; where the multiple double-bonds of PUFAs renders them particularly susceptible to oxidation (e.g. in supplements ¹⁸, stomach ^132,133 and LDL ¹³⁴). Both blood ^3,14,68 and LDL lipids ^23,63,64,128 are high in linoleic acid (C18:2, n-6), especially in cholesteryl esters (e.g. PL/TG ~20%, CE ~50% ³). Accordingly, trials with higher MUFAs ^135–138 or lower total/saturated fat ^{5,135,139,140} have lowered lipoprotein oxidation (i.e. MDA/dienes in vitro/vivo) or plasma isoprostanes ¹³⁸, in relation to LDL quality (i.e. C18:1/18:2 ratio) ^{135,136,138,140} or quantity (e.g. LDL-c/apoB) ^5,139,140. Also, while LDL particle size and free cholesterol were associated with lower oxidative susceptibility ¹²⁵, in vivo LDL oxidation (antibody method) and in vitro proteoglycan-binding strongly correlated many apoB-100 lipoproteins and their lipids, especially in smaller VLDLs (e.g. Fig. 4) ¹³¹, unlike LDL aggregation (which correlates PC/SM, as above) ^130,131,141. Moreover, all PUFAs may not be equal; habitual intake and LDL content of omega-6 and 3 (esp. C18:2 and 22:6) correlated higher and lower LDL oxidation sensitivity, respectively ⁶³. Further, RCTs with omega-3s generally improve blood redox markers ¹⁴²; and even in advanced atherosclerotic plaques, omega-3 (esp. EPA) content is increased with supplementation and correlates greater stability and lower inflammation ^143,144. Accordingly, compared to various fatty acids, omega-3s (esp. EPA) had the greatest antioxidant activity on micelles ¹⁴⁵ and small-dense LDL ¹⁴⁶, and EPA/DHA best suppressed ROS in endothelial cells ¹⁴⁵. Also, oxidation of omega-6 and 3s generates different products ^134,147 with different effects; e.g. DHA-derived 4-HHE can activate the Nrf2/HO-1 antioxidant pathway in multiple organs ¹⁴⁸, while AA-derived 4-HNE associates more with inflammation ¹⁴⁹, consistent with typical immunomodulatory paradigms. Ultimately, since omega-3s are particularly sensitive to oxidation, this may make them ideal redox sensors, coupling antioxidant metabolism to preservation of PUFAs and membrane biophysics ¹⁵⁰.

Pathological biophysics

Many diseases are associated with dysregulated lipid metabolism and biophysics, foremost cardiovascular disease (CVD) ¹⁰⁹. CVD is typically driven by atherosclerosis, which largely involves accumulation of lipids (esp. cholesterol) in the artery wall (esp. intimal foam cells), alongside lipoprotein particles (esp. apoB) ^{114,151–153}. In animal models, a SFA-rich diet greatly increases arterial uptake of whole LDL and cholesteryl esters (i.e. selective uptake), in association with plasma cholesterol ¹⁵⁴ and (macrophage) lipoprotein lipase ¹⁵⁵, and in contrast to n-3 PUFAs ^155,156. As above, SFAs (vs. UFAs) may also favour LDL aggregation and proteoglycan-binding, and therefore arterial retention ¹³¹. Exposure of cells to apoB-lipoproteins can induce ‘foamy’ cells with abundant lipid droplets of cholesteryl esters; e.g. macrophages incubated with native (high level) ^157,158, aggregated ^159,160 or multi-modified LDL ^161,162; and perhaps less so (heavily) oxidised LDL ^{157,159–161,163}, which induces lysosomal accumulation of cholesterol-sphingomyelin particles, due to inhibition of sphingomyelinase by 7-ketocholesterol ¹⁶⁴. Importantly, the presence of cholesterol crystals is also a hallmark of atheroma ^114,152, in association with extracellular lipoprotein particles and foam cells ^153,165. In particular, in human aorta, transition from fatty streak to fibroatheroma (i.e. early–late stage) was associated with smooth muscle cell crystallisation and death ¹⁶⁵. Further, in models of diet-induced atherosclerosis, crystals appeared early in endothelium ^166,167 and increasingly macrophages ¹⁶⁸, and caused lysosomal destabilisation and NLRP3 inflammasome activation ^169–171; thus linking hyperlipidaemia to inflammation. Moreover, sustained exposure to LDL induces endothelial crystallisation ¹⁶⁶, which is exacerbated by synergy between inflammatory cytokines (i.e. LDL + IFNg/TNFα), alongside suppression of esterification ¹⁶⁷; while examples of higher peripheral inflammation with lower atherosclerosis attest a dependence on other risk factors/lipids ^172,173. Oxidised LDL also induces macrophage phago-lysosomal crystals and NLRP3 activation ^163,170,174; while in model membranes cholesterol crystal domains are induced by oxidation and inhibited by omega-3s (esp. EPA/DPA) ¹⁴⁶. Notably, plaque crystals co-associated with cholesterol microdomains ¹⁶⁸, which may be shed from macrophage plasma membranes ¹⁷⁵; while excess free cholesterol in macrophages induced extracellular crystals and cytotoxicity offset by extracellular acceptors (i.e. apoA-1/E) mediating efflux of cholesterol from plasma membrane ^176,177. In particular, the ABCA1 transporter may associate with cholesterol-rich lipid rafts ¹⁷⁸ to mediate efflux to nascent HDL ¹⁷⁹ and suppress raft-associated TLR/inflammatory signalling ^180–182.

In humans and animals, intensive lipid-lowering can induce athero-regression ¹⁸³, which may involve a net efflux of cholesterol via reverse cholesterol transport ^184,185. Notably, trials with various unsaturated oils have lowered carotid thickening (i.e. cIMT) ¹⁸⁶ and increased cholesterol efflux (in vitro) ¹⁴ in relation to plasma ¹⁶ or HDL fluidity ¹⁸⁷; with some trends for omega-3 superiority ^14,186. A rate-limiting step for efflux is cholesteryl ester hydrolysis to free cholesterol, which is faster with liquid-state (isotropic) esters ¹⁸⁸ and supported by lysosomal delivery of triglycerides (via VLDL or triolein) ¹⁸⁹. Accordingly, diet can increase omega-3 content in blood/LDL cholesteryl esters ^3,14,63,64, which in triglyceride-depleted macrophages associated with increased fluidity, hydrolysis and efflux ¹⁸⁸. Incorporation of omega-3s into membrane phospholipids may also move cholesterol from the inner to outer leaflet ^81,188, an optimal position for efflux ¹⁹⁰. Moreover, serum from people on omega-3 inhibited lipogenic genes in monocytes (i.e. SCD and FADS2) ⁸⁹ and foam cells (i.e. SCD-1) ⁸¹; and α-linolenic acid (C18:3, n-3) modulation of an FXR–SCD-1 pathway decreased cholesterol storage and increased efflux ^81,191. Also, chylomicron remnants loaded with triglycerides rich in n-6 or n-3 PUFAs (vs. MUFAs/SFAs) best suppressed macrophage NF-kB/COX-2 and increased cholesterol efflux, which may be linked ¹⁹². Note, in the dietary fat trials above, cholesterol efflux seemed unaffected by increased LDL oxidation ^14,136 (these studies = same design), but was markedly blunted with higher BMI ¹⁶ or CRP ⁸¹; while immune-associated and myeloperoxidase-induced HDL oxidation has been linked to CVD and HDL dysfunction, including impaired cholesterol efflux via ABCA1 ¹⁹³.

Importantly, beyond CVD, cholesterol accumulation and crystallisation are implicated in many other tissues/diseases ¹⁰⁹. For instance, hepatic cholesterol is elevated in NAFLD, while the presence of crystals in lipid droplets is specifically associated with NASH ¹⁹⁴. Accordingly, in preclinical models, hepatocyte lipid droplets represent the major repository of cholesterol, where excess free cholesterol can precipitate and crystallise ^194,195, resulting in cell death and inflammation, underlying the appearance of ‘crown-like’ structures and foam cells, and transition from NAFLD to NASH ^108,194,195. In these models crystallisation is induced by the combination of dietary fat and cholesterol ^108,195,196, and exacerbated by PCSK9 deletion (increases LDLR) ¹⁹⁷, or can be induced in vitro with oleic acid and sustained LDL exposure ^194,195, indicating a synergistic effect of fat and cholesterol, as with LDLR regulation above ⁶⁹. Note, crown-like structures were originally reported in adipose during obesity, where crystals may also be implicated ¹⁹⁸. Also, age-related thymic involution is associated with lipid accumulation, adipogenesis and NLRP3 activation, all of which was linked to macrophage-associated ceramides and free cholesterol ¹⁹⁹; while macrophage crystals have also been reported (i.e. Fig. 4) ²⁰⁰. Conversely, a 2-year RCT with 14% caloric restriction improved thymopoiesis, in association with mobilisation of ectopic lipid and suppression of adipose PLA2G7 targeting NLRP3 ²⁰¹. In the CNS, myelin is particularly rich in cholesterol, which may be liberated by injury. Accordingly, in the aged mouse, myelin damage induced a defective remyelination response, accompanied by sustained immune infiltration and foam cells with lipid droplets and cholesterol crystals, which was restored by stimulating reverse cholesterol transport ²⁰². And in the eye, early stages of age-related macular degeneration (AMD) are characterised by accumulation of lipid-rich drusen, where the presence of crystals (i.e. the ‘onion sign’) may be indicative of progression to vision loss (i.e. drusen end-stages) ²⁰³. Conversely, a small trial with high-dose statins induced regression of drusen with vision gain in some people ²⁰⁴.

The brain and retina are particularly rich in lipids and PUFAs, the balances of which may be disrupted in ageing and disease, and of consequence to membrane physiology ^{150,205–208}. For instance, in human orbitofrontal cortex, an age-related decline in PUFAs (esp. AA and DHA) correlated increased SCD activity (i.e. mRNA and SFA/MUFA ratios) ²⁰⁹; which may also occur in Alzheimer’s disease (AD) ²¹⁰. Further, frontal cortex lipid rafts may undergo gender-specific changes during ageing, which was generally associated with decreasing cholesterol and n-6 PUFA content ²¹¹. And in early-stage sporadic AD, frontal and entorhinal lipid rafts had many deficits, including lower cholesterol, sphingomyelin, unsaturation (n-9 and n-3) and peroxidability indexes ²¹²; alongside greater liquid-order and viscosity, which correlated decreased n-3 PUFAs and increased BACE1­–APP interaction, potentially facilitating amyloid-β (Aβ) production ^212,213. Preclinical models suggest lipid rafts increase in viscosity and size with ageing, which is exacerbated in familial AD, potentially favouring coalescence of amyloidogenic machinery, and offset by cholesterol and PUFAs ²¹⁴. In particular, DHA modulates membrane cholesterol/phase separation ^93,94, neuro-receptor partitioning ²¹⁵ and Aβ processing ²¹⁶. Conversely, in familial AD, elevated cellular and lipid raft cholesterol may promote APP localisation ²¹⁷. Moreover, the most important risk factor for sporadic AD is genetic variation in apoE, which employs astrocyte-derived cholesterol to traffic APP in and out of neuronal lipid rafts, controlling production of neurotoxic Aβ vs. neuroprotective sAPP-α, respectively ²¹⁸; the former being favoured by apoE4 ²¹⁹. A potential reconciliation to these divergent findings is that lipid raft APP localisation/processing is ultimately tied to viscosity, which can be increased by low unsaturation or high cholesterol ^213,214. Notably, retinal PUFAs and Aβ are also implicated in AMD, suggesting overlapping pathology ²²⁰.

Finally, the gut microbiome is a potential source of inflammation in ageing and disease. As above, dietary SFAs promote and omega-3s suppress postprandial translocation of bacterial LPS from gut to blood ²²¹, potentially via differential modulation of enterocyte lipid raft-associated TLR signalling ¹⁰⁴. Similarly, SFAs promote and omega-3s suppress bile-related outgrowth of sulphite-reducing (Gram-negative) Bilophila ⁵⁴, along with gut inflammation and permeability ^52–54; and in association with SFA-induced liver fat ²²². Microbial lipids can be transported to blood via portal­­ or lymph pathways ²²³. In blood, Gram-negative LPS and Gram-positive LTA have affinity for all lipoproteins ²²⁴, especially HDL ²²⁵, and are subsequently transferred to LDL ^226,227, while the hepatic LDLR plays a major role in their clearance ^228,229. LPS binding to lipoproteins suppresses acute toxicity, although may still transport bioactive LPS into tissues, including lymph nodes ²³⁰, adipose ²³¹ and endothelium ²³², where it may induce inflammation. In particular, LPS acts as a priming signal for inflammasomes, facilitating activation by cholesterol crystals ^153,165; and also promotes LDL oxidation by copper ions, endothelial and smooth muscle cells ²³³. Furthermore, in animals, dietary SFAs (not MUFAs or PUFAs) also induce intestinal (enterocyte) and plasma Aβ ²³⁴, where it associates with triglyceride-rich lipoproteins (potentially as a regulating apolipoprotein ²³⁵) and is capable of inducing neurovascular dysfunction ^236,237. Notably, Aβ also increases macrophage uptake of LDL, intracellular free and esterified cholesterol, and foam cell formation ²³⁸. Conversely, peripheral Aβ is cleared by liver LDLR and LRP1, which may also facilitate clearance of brain Aβ ^239–241.

Perspective

In summary, dietary fats have differential effects on the body, attributable to various pathways and their regulation—but under what forces? This post explored a biophysical perspective. Accordingly, fatty acids have diverse physiochemical properties which underlie specific biophysical behaviours in aqueous and lipid compartments of the body, including that of lipid-based biomolecules mediating storage/transport and structure/function (e.g. lipoproteins and membranes, respectively). As such, cells may require tight regulation of specific fatty acid balances to maintain lipid behaviours conducive to normal physiology; while the physiochemical heterogeneity of dietary fats may present a constant homeostatic challenge, requiring rapid/dynamic adaptive responses to maintain short-term fitness, and modulating long-term health across environments and genetic adaptations. Ultimately, differential effects may arise from modulation of fatty acid levels and counter-regulatory pathways serving to maintain biophysical homeostasis; a perspective which might help explain prominent effects on gut and liver (i.e. 2 initial diet buffers), and downstream cardiovascular and neurological consequences, amongst others.

Most notoriously, saturated fat elevates blood cholesterol—but why, and does it matter? As above, perhaps this could involve suppression of LDLR activity via free cholesterol and membrane physiology, and represent extracellular backlog from a constrained effort to maintain the lipid unsaturation and fluidity favoured by evolution, which long-term promotes ectopic lipid accumulation and age-related biophysical dysfunction and disease?

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