Interaction of gut microbiota with dysregulation of bile acids in the pathogenesis of nonalcoholic fatty liver disease and potential therapeutic implications of probiotics

The intestinal microbiota is now recognised to play key roles in health due to its involvement in many aspects of human physiology. Disturbance in gut microbiota (dysbiosis) is thus associated with many diseases including nonalcoholic fatty liver disease (NAFLD) which includes nonalcoholic fatty liver and nonalcoholic steatohepatitis. The mechanisms for the effect of dysbiosis in NAFLD pathogenesis are not completely elucidated. Many explanations have been proposed to trigger dysbiosis, leading to NAFLD including inflammation, ethanol produced by the gut bacteria and lipotoxicity. Recently the roles of bile acids and nuclear receptors are highly regarded. It is well known that gut microbes produce enzymes that convert primary bile acids into secondary bile acids in the intestines. Several studies have demonstrated that disturbance of the intestinal microbiota leads to decreased synthesis of secondary bile acids, which in turn decreases activation of nuclear receptors such as farnesoid X receptor (FXR), pregnane X receptor, Takeda G-protein–coupled bile acid protein 5 and vitamin D receptor. These receptors are important in energy regulation and their dysregulation can cause NAFLD. Therefore, stimulation of nuclear receptors especially FXR has been extensively explored for the amelioration of NAFLD. However, paradoxical effects of nuclear receptor activation are a major problem for the clinical application of nuclear receptor stimuli. We further posit that microbiome restoration could be an alternative approach for the treatment of NAFLD. Several gut bacteria are now known to be involved in bile acid metabolism. It will be necessary to identify which one/ones is/are feasible. Careful selection of commensal bacteria for probiotics may lead to an effective therapy for NAFLD.     

Effects of saturated and unsaturated fats given with and without dietary cholesterol on hepatic cholesterol synthesis and hepatic lipid metabolism

Hepatic cholesterol synthesis was studied in rats after consuming diets of varying neutral lipid and cholesterol content. Cholesterol synthesis was evaluated by measuring 3-hydroxy-3-methylglutaryl-CoA reductase and by determining the rate of 3H-labeled sterol production from [3H]mevalonate. Results were correlated with sterol balance data and hepatic lipid content. Hepatic cholesterol synthesis was relatively great when cholesterol was excluded from the diet. The source of neutral dietary lipids, saturated vs. unsaturated, produced no change in hepatic sterol synthesis. Values for fecal sterol outputs and hepatic cholesterol levels were also similar in rats consuming either saturated or unsaturated fats. When 1% cholesterol was added to the diet, hepatic cholesterol synthesis was suppressed but the degree of suppression was greater in rats consuming unsaturated vs. saturated fats. This was associated with greater accumulation of cholesterol in livers from rats consuming unsaturates and a reduction in fecal neutral sterol output in this group as opposed to results from rats on saturated fats. Cholesterol consumption also altered the fatty acid composition of hepatic phospholipids producing decreases in the percentages of essential polyunsaturated fatty acids. It is concluded that dietary cholesterol alters cholesterol and fatty acid metabolism in the liver and that this effect is enhanced by dietary unsaturated fats.     

Djungarian hamsters exhibit temperature-dependent dietary fat choice in long days

Previous studies have shown that whole-animal thermal responses of ectotherms and heterotherms (e.g., hibernators), both of which experience a wide range of body temperatures, are related to the saturation level of somatic lipids, which in turn can be influenced by the ratio of saturated and unsaturated fatty acids in the diet. This study demonstrates that Djungarian hamsters held in long days display ambient temperature-dependent choice of dietary fats, increasing their preference for saturated fats when ambient temperature increases (to 27 degrees C) and later reversing this preference when ambient temperature is returned to its original value (8 degrees C). Changes in percent contribution of the unsaturated and saturated diets in response to temperature were accomplished almost solely by changes in the amount of unsaturated diet consumed. Temperature-dependent fatty acid choice occurs at a stage in the annual cycle when Djungarian hamsters do not enter spontaneous daily torpor and therefore experience only small changes in core body temperature. These results suggest that temperature-dependent fatty acid choice may occur in a wide range of animals, including nonheterothermic endotherms.     

Lizards, lipids, and dietary links to animal function

Our experiments were designed to test the hypotheses that dietary lipids can affect whole-animal physiological processes in a manner concordant with changes in the fluidity of cell membranes. We measured (1) the lipid composition of five tissues, (2) body temperatures selected in a thermal gradient (T(sel)), (3) the body temperature at which the righting reflex was lost (critical thermal minimal [CTMin]), and (4) resting metabolic rate (RMR) at three body temperatures in desert iguanas (Dipsosaurus dorsalis) fed diets enriched with either saturated or unsaturated fatty acids. The composition of lipids in tissues of the lizards generally reflected the lipids in their diets, but the particular classes and ratios of fatty acids varied among sampled organs, indicating the conservative nature of some tissues (e.g., brain) relative to others (e.g., depot fat). Lizards fed the diet enriched with saturated fatty acids selected warmer nighttime body temperatures than did lizards fed a diet enriched with unsaturated fatty acids. This difference is concordant with the hypothesis that the composition of dietary fats influences membrane fluidity and that ectotherms may compensate for such changes in fluidity by selecting different body temperatures. The CTMin of the two treatment groups was indistinguishable. This may reflect the conservatism of some tissues (e.g., brain) irrespective of diet treatment. The RMR of the saturated treatment group nearly doubled between 30 degrees and 40 degrees C. Here, some discrete membrane domains in the lizards fed the saturated diet may have been in a more-ordered phase at 30 degrees C and then transformed to a less-ordered phase at 40 degrees C. In contrast, the RMR of the unsaturated treatment group exhibited temperature independence in metabolic rate from 30 degrees to 40 degrees C. Perhaps the unsaturated diet resulted in membranes that developed a higher degree of disorder (i.e., a certain phase) at a lower temperature than were membranes of lizards fed the saturated diet. Our study demonstrates links between dietary fats and whole-animal physiology; however, the mechanistic basis of these links, and the general knowledge of lipid metabolism in squamate reptiles, remain poorly understood and warrant further study.     

膳食脂肪对肠道微生物的影响及宿主代谢调控的研究进展

膳食脂肪作为人体重要的营养物质之一,为人体提供能量及营养。不同种类的膳食脂肪对宿主肠道微生物的组成和数量的影响有着明显的差异。同时肠道微生物又能参与宿主的代谢调控以及影响肠道屏障功能等。过多的摄入富含饱和脂肪酸的膳食脂肪会引起肠道中厚壁菌门、变形菌门、梭菌属等的增加,从而影响宿主代谢过程中的胆汁酸等信号分子改变,导致肠道通透性的增加和系统炎症。富含n-3多不饱和脂肪酸的膳食脂肪会引起肠道中双歧杆菌和乳杆菌的增加,从而影响宿主代谢过程中的短链脂肪酸的水平,某些短链脂肪酸能够调控宿主的胰岛素分泌以及炎症因子的表达。本文综述了膳食脂肪的种类、肠道微生态和宿主代谢调控之间的相互作用及其可能的作用机制,为深入了解饮食、肠道微生态、宿主健康三者之间的关系提供了依据。     

Diet preferences of warblers for specific fatty acids in relation to nutritional requirements and digestive capabilities

During energy-demanding periods of the annual cycle such as migration or during cold days in winter, birds store fat comprised mostly of 16- or 18-carbon unsaturated fatty acids. In such situations, birds may feed selectively on foods with specific fatty acids that enable efficient fat deposition. We offered wild-caught yellow-rumped warblers Dendroica coronata paired choices between semi-synthetic diets that differed only in their fatty acid composition. Warblers strongly preferred diets containing long-chain (18:1; carbon atoms:double bonds) unsaturated, unesterified fatty acids to diets containing long-chain saturated, unesterified fatty acids (18:0) and they preferred diets containing mono-unsaturated fats (18:1) to diets containing poly-unsaturated fats (18:2). The preference for diets containing long-chain unsaturated fatty acids to diets containing long-chain saturated fatty acids was consistent in birds tested one week after capture at 21°C, one month after capture when cold-acclimated (1°C), and six weeks after capture at 21°C. Birds acclimated to a diet with 50% of the fat comprised of unesterified stearic acid (18:0) lost mass and reduced their food intake when we reduced ambient temperature from 21°C to 11°C over three days. We conclude that especially in energy-demanding situations there are limits to the yellow-rumped warblers' ability to assimilate some long-chain saturated fatty acids and that this digestive constraint can explain in part why yellow-rumped warblers prefer diets containing long-chain unsaturated fatty acids to diets containing long-chain saturated fatty acids.     

The digestion of dietary triacylglycerols

Dietary triacylglycerols (TAGs) are the major lipid components in the human diet and they are carriers of energy as well as important fatty acids. Many factors affect the digestion and absorption of TAGs. Evidence is accumulating that, in addition to the overall fatty acid profile, the TAG structure and the species composition are of importance when considering the nutritional effects of a dietary fat. There is good evidence that in addition to its short-term effects in the intestine on absorption of fatty acids the TAG structure also has long-term effects resulting from differences in the profile of absorbed fatty acids. Observations on the different atherogenic potential of dietary fats have given us a clear indication of the importance of the TAG structure for absorption of saturated fatty acids. In this context, one may focus on the effects of the structure of dietary fats as such, or one may speculate additionally on the possibilities of modifying the structure of fats to affect their absorption and the distribution of the fatty acids in the body after digestion and uptake. In this review we will summarize diverse aspects of TAG digestion and absorption, as well as the influences of the fatty acid composition and the intramolecular structure of dietary TAGs on their digestion and absorption.     

The effect of ionizing radiation on the fatty acid composition of natural fats and on lipid peroxide formation.

The effects of irradiation doses of 200-1000 krad on the fatty acid compositions of saturated and unsaturated natural food fats have been studied. Lard, coconut oil, corn oil, methyl linoleate and herring oil have been analysed before and after irradiation for lipid peroxide content and fatty acid composition. The effects of storage under varied conditions after irradiation have also been investigated. Irradiation doses of 200-1000 krad had little effect on the fatty acid compositions of saturated fats (lard and coconut oil) or of fats with a high antioxidant content (corn oil) but caused destruction of 98 per cent of the highly unsaturated acids (18: 4,20 :5,22 : 6) and 46 per cent of the diene acids (18:2) in herring oil. The destruction of the polyunsaturated fatty acids increased with increasing storage temperature and storage time. The destruction of polyunsaturated fatty acids is accompanied by an increase in lipid peroxide formation. It is considered that changes in fatty acid composition in natural foods after irradiation are important in consideration of the use of irradiation for food preservation.     

The interaction of dietary fatty acid and cholesterol on catecholamine-stimulated adenylate cyclase activity in the rat heart

Diets supplemented with high levels of saturated or unsaturated fatty acids supplied by addition of sheep kidney fat or sunflower seed oil, respectively, were fed to rats with or without dietary cholesterol. The effects of these diets on cardiac membrane lipid composition, catecholamine-stimulated adenylate cyclase and beta-adrenergic receptor activity associated with cardiac membranes, were determined. The fatty acid-supplemented diets, either with or without cholesterol, resulted in alterations in the proportion of the (n-6) to (n-3) series of unsaturated fatty acids, with the sunflower seed oil increasing and the sheep kidney fat decreasing this ratio, but did not by themselves significantly alter the ratio of saturated to unsaturated fatty acids. However, cholesterol supplementation resulted in a decrease in the proportion of saturated and polyunsaturated fatty acids and a dramatic increase in oleic acid in cardiac membrane phospholipids irrespective of the nature of the dietary fatty acid supplement. The cholesterol/phospholipid ratio of cardiac membrane lipids was also markedly increased with dietary cholesterol supplementation. Although relatively unaffected by the nature of the dietary fatty acid supplement, catecholamine-stimulated adenylate cyclase activity was significantly increased with dietary cholesterol supplementation and was positively correlated with the value of the membrane cholesterol/phospholipid ratio. Although the dissociation constant for the beta-adrenergic receptor, determined by [125I](-)-iodocyanopindolol binding, was unaffected by the nature of the dietary lipid supplement, the number of beta-adrenergic receptors was dramatically reduced by dietary cholesterol and negatively correlated with the value of the membrane cholesterol/phospholipid ratio. These results indicate that the activity of the membrane-associated beta-adrenergic/adenylate cyclase system of the heart can be influenced by dietary lipids particularly those altering the membrane cholesterol/phospholipid ratio and presumably membrane physico-chemical properties. In the face of these dietary-induced changes, a degree of homeostasis was apparent both with regard to membrane fatty acid composition in response to an altered membrane cholesterol/phospholipid ratio, and to down regulation of the beta-adrenergic receptor in response to enhanced catecholamine-stimulated adenylate cyclase activity.     

Dietary fats and membrane function: implications for metabolism and disease

Lipids play varied and critical roles in metabolism, with function dramatically modulated by the individual fatty acid moities in complex lipid entities. In particular, the fatty acid composition of membrane lipids greatly influences membrane function. Here we consider the role of dietary fatty acid profile on membrane composition and, in turn, its impact on prevalent disease clusters of the metabolic syndrome and mental illness. Applying the classical physiological conformer-regulator paradigm to quantify the influence of dietary fats on membrane lipid composition (i.e. where the membrane variable is plotted against the same variable in the environment--in this case dietary fats), membrane lipid composition appears as a predominantly regulated parameter. Membranes remain relatively constant in their saturated (SFA) and monounsaturated (MUFA) fatty acid levels over a wide range of dietary variation for these fatty acids. Membrane composition was found to be more responsive to n-6 and n-3 polyunsaturated fatty acid (PUFA) levels in the diet and most sensitive to n-3 PUFA and to the n-3/n-6 ratio. These differential responses are probably due to the fact that both n-6 and n-3 PUFA classes cannot be synthesised de novo by higher animals. Diet-induced modifications in membrane lipid composition are associated with changes in the rates of membrane-linked cellular processes that are major contributors to energy metabolism. For example, in the intrinsic activity of fundamental processes such as the Na+/K+ pump and proton pump-leak cycle. Equally, dietary lipid profile impacts substantially on diseases of the metabolic syndrome with evidence accruing for changes in metabolic rate and neuropeptide regulation (thus influencing both sides of the energy balance equation), in second messenger generation and in gene expression influencing a range of glucose and lipid handling pathways. Finally, there is a growing literature relating changes in dietary fatty acid profile to many aspects of mental health. The understanding of dietary lipid profile and its influence on membrane function in relation to metabolic dysregulation has exciting potential for the prevention and treatment of a range of prevalent disease states.