Wednesday, 30 March 2016

How saturated fats induce inflammation

Saturated fats comprise a group of fatty acids of varying lengths (chains of C) which are fully ‘saturated’ with hydrogen atoms (no C double bonds). This structure makes the longer chained saturated fats solid at room temperature. In the diet, saturated fats are most abundant in animal foods (e.g. fatty meats, butter and dairy), as well as a few plant foods (e.g. coconut oil and cocoa butter).

Saturated fats have long been studied for how they may promote disease. Much focus has been on the ability of saturated fat to raise cholesterol, and therefore (controversial) connections with cardiovascular disease (CVD) 1–3. There has also been substantial research into the ability of saturated fats and their metabolites to impair insulin sensitivity and induce cell death (i.e. lipotoxicity) 4. Most recently, the effects of saturated fats on the gut microbiota and immune system are being revealed, which extends the relevance to immunological diseases, as reviewed below.

Gut dysbiosis
Effect of several foods on postprandial 
endotoxin (LPS) levels and NF-kB 
binding in healthy volunteers.
The gut contains the largest mass of immune tissue in the body (gut-associated lymphoid tissue), which is shaped by the resident gut microbiota. Unlike sugars and amino acids, fats are not extensively metabolised by the gut microbiota; however they do greatly alter the intestinal environment. Diets high in saturated fats (e.g. lard, tallow or dairy) or omega-6 (e.g. corn and sunflower oil) induce gut dysbiosis and inflammation, which can be opposed by omega-3s (fish oil) 5–7. Saturated fats in particular may induce an overgrowth of bile-resistant, sulfur-reducing bacteria, with increased inflammatory potential 6,7.

LPS translocation
The gut microbiota is separated from the rest of the body by the gut barrier (mucus and epithelium). Diet greatly influences the permeability (‘leakiness’) of the gut barrier to bacteria and their antigens (e.g. LPS/endotoxin). In animals and humans, high energy/fat meals induce a postprandial (0-5hr) increase in blood LPS 8–10, inflammation and oxidative stress 11–13. Several studies implicate saturated fat as the main culprit 7,8,10,14. For instance in humans, blood LPS was increased by 30g of cream (70% sat fat), but not orange juice or glucose 12; in an animal study, blood LPS was increased by porridge made with coconut oil (89% sat fat), but decreased by fish oil (omega-3), while vegetable oil was without significant effect 14.

Several mechanisms have been identified by which high fat diets can increase intestinal permeability. For the transcellular (through cell) route, fats can increase enterocyte membrane permeability (via lipid rafts 14) and intracellular transport via chylomicrons 8. For the paracellular (between cells) route, high fat diets increase bile secretion which can decrease epithelial integrity 15 and colonic tight junction expression 16.

Inflammatory signaling
LPS, aka. endotoxin
LPS binds to toll-like receptor 4 (TLR4), expressed on the surface of many cell types, to activate inflammatory signaling. LPS (lipopolysaccharide) is so named because it contains fat (lipid) and carbohydrate (polysaccharide). Saturated fats (C12-14) acylated in the lipid A portion of LPS are essential for signaling via TLR4; and similarly for lipopeptide signaling via TLR2 17. Moreover, free saturated fats (e.g. palmitic and lauric acid) can directly stimulate TLR4/2 signaling (via receptor dimerization and translocation into lipid rafts), which can be inhibited by DHA (omega-3) 17–20. Similarly, palmitic acid primes/activates the intracellular NF-kB and NLRP3 inflammasome pathways, while DHA inhibits them 21.

Direct modulation of inflammatory signaling by fatty acids could have relevance to many body tissues. In the gut, free fatty acids (FFAs) are liberated during digestion (by pancreatic lipase). Systemically, diet/activity influences cell membrane lipid composition and release of FFAs into blood by adipose tissues. In humans, elevated blood FFAs are seen in many metabolic diseases, with their deleterious effects (including inflammation and insulin resistance) attributable to saturated fat content (e.g. palmitate and stearate) 22. Saturated FFAs can also cross the blood-brain barrier, impair neuronal energy metabolism 23 and activate astrocytes (neuroinflammation) 20.

Beyond inflammation, saturated fats have been linked to autoimmune disease. Fats can modulate T and B cells via indirect (e.g. gut microbiota) and direct mechanisms (e.g. signaling pathways). A recent animal study showed that dietary long-chain saturated fats (palmitic and lauric acid) promote Th1 and Th17-based CNS autoimmunity (EAE). This was accompanied by suppression of intestinal SCFAs, which normally induce Treg activity and prevent autoimmunity 24. Notably in humans, Dr Swank published repeatedly on a link between increased fat consumption and MS, while a low cholesterol diet was recently shown to lower autoimmune potential (Th17/Treg balance) in people with hepatitis C 25.

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2.         de Souza, R. J. et al. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies. BMJ 351, h3978 (2015).
3.         Hooper, L., Martin, N., Abdelhamid, A. & Davey Smith, G. Reduction in saturated fat intake for cardiovascular disease. Cochrane database Syst. Rev. 6, CD011737 (2015).
4.         Estadella, D. et al. Lipotoxicity: effects of dietary saturated and transfatty acids. Mediators Inflamm. 2013, 137579 (2013).
5.         Ghosh, S. et al. Fish oil attenuates omega-6 polyunsaturated fatty acid-induced dysbiosis and infectious colitis but impairs LPS dephosphorylation activity causing sepsis. PLoS One 8, e55468 (2013).
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19.       Wong, S. W. et al. Fatty acids modulate Toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner. J. Biol. Chem. 284, 27384–92 (2009).
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21.       Sui, Y.-H., Luo, W.-J., Xu, Q.-Y. & Hua, J. Dietary saturated fatty acid and polyunsaturated fatty acid oppositely affect hepatic NOD-like receptor protein 3 inflammasome through regulating nuclear factor-kappa B activation. World J. Gastroenterol. 22, 2533–44 (2016).
22.       Pararasa, C., Bailey, C. J. & Griffiths, H. R. Ageing, adipose tissue, fatty acids and inflammation. Biogerontology 16, 235–48 (2015).
23.       Kwon, B. & Querfurth, H. W. Opposite effects of saturated and unsaturated free fatty acids on intracellular signaling and metabolism in neuronal cells. Inflamm. Cell Signal. 1, 10–14800/ics.200 (2014).
24.       Haghikia, A. et al. Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine. Immunity 43, 817–829 (2015).
25.       Maggio, R. et al. Normocaloric low cholesterol diet modulates Th17/Treg balance in patients with chronic hepatitis C virus infection. PLoS One 9, e112346 (2014).

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