胆汁酸对代谢性疾病的调控

胆汁酸作为一种信号分子通过激活肝、肠道和外周组织中的胆汁酸受体影响体内葡萄糖和脂质的代谢平衡,对于调节肥胖、2型糖尿病和非酒精性脂肪肝等代谢性疾病具有非常重要的意义。胆汁酸与相应核受体,如法尼醇X受体(farnesoid X receptor, FXR)和Takeda G蛋白偶联受体5 (Takeda G protein-coupled receptor 5,TGR5)的相互作用影响了这些代谢性疾病。FXR主要通过影响胆汁酸的合成及转运对非酒精性脂肪肝发挥作用,TGR5则是间接增加褐色脂肪组织中的生热作用,改善肥胖和2型糖尿病。这些调控机制的研究是非常必要的。本文综述了胆汁酸代谢及其对代谢性疾病调控的分子机制的研究进展,以期为科研工作者提供一定的参考。     

Effects of fish oil on hypertension, plasma lipids, and tumor necrosis factor-alpha in rats with sucrose-induced metabolic syndrome

Dietary fish oil rich in (n-3) fatty acids plays an important role in reducing abnormalities associated with the metabolic syndrome and mortality from coronary heart disease. We investigated the effects of dietary fish oil on the metabolic syndrome in a high-sucrose-fed rat model. The model was achieved by the administration of 30% sucrose in drinking water in male Wistar rats during 21 weeks. After the metabolic syndrome rat model was established, fish oil was administered during 6 weeks. The metabolic syndrome rats showed significant increases in body weight, systolic blood pressure, serum insulin, total lipids, triacylglycerols, cholesterol, free fatty acids, LDL, total proteins, albumin, and serum tumor necrosis factor-alpha (TNF-alpha). They also presented abdominal and epididymal fat accumulation and fatty liver. After fish oil diet administration, metabolic syndrome rats had a significant reduction in blood pressure, serum insulin, triacylglycerols, cholesterol, free fatty acids, and total lipids, but no change was observed in TNF-alpha concentration or fat accumulation. In conclusion, fish oil reversed the alterations on metabolic parameters and blood pressure exerted by sucrose administration, although it had no effect on TNF-alpha production and adiposity. This confirms the theory that the molecular etiology of the metabolic syndrome is multifactorial, as is the effect of n-3 polyunsaturated fatty acids (PUFAs) upon it, having complex and multifaceted actions.     

Effects of ALA,EPA and DHA in high-carbohydrate,high-fat diet-induced metabolic syndrome in rats

We compared the cardiovascular, hepatic and metabolic responses to individual dietary n-3 fatty acids (α-linolenic acid, ALA; eicosapentaenoic acid, EPA; and docosahexaenoic acid, DHA) in a high-carbohydrate, high-fat diet-induced model of metabolic syndrome in rats. Additionally, we measured fatty acid composition of plasma, adipose tissue, liver, heart and skeletal muscle in these rats. The same dosages of ALA and EPA/DHA produced different physiological responses to decrease the risk factors for metabolic syndrome. ALA did not reduce total body fat but induced lipid redistribution away from the abdominal area and favorably improved glucose tolerance, insulin sensitivity, dyslipidemia, hypertension and left ventricular dimensions, contractility, volumes and stiffness. EPA and DHA increased sympathetic activation, reduced the abdominal adiposity and total body fat and attenuated insulin sensitivity, dyslipidemia, hypertension and left ventricular stiffness but not glucose tolerance. However, ALA, EPA and DHA all reduced inflammation in both the heart and the liver, cardiac fibrosis and hepatic steatosis. These effects were associated with complete suppression of stearoyl-CoA desaturase 1 activity. Since the physiological responses to EPA and DHA were similar, it is likely that the effects are mediated by DHA with EPA serving as a precursor. Also, ALA supplementation increased DHA concentrations but induced different physiological responses to EPA and DHA. This result strongly suggests that ALA has independent effects in metabolic syndrome, not relying on its metabolism to DHA.     

Dietary minerals and modification of cardiovascular risk factors

High serum cholesterol, hypertension and obesity are major risk factors for cardiovascular diseases, and together with insulin resistance form a deadly disorder referred to as the metabolic syndrome. All the aspects of this syndrome are strongly related to dietary and lifestyle factors; therefore, it would be reasonable to look for dietary approaches to their modification. Mineral nutrients, such as calcium, potassium and magnesium, lower blood pressure, and especially calcium has beneficial effects also on serum lipids. Recent evidence suggests that increased intake of calcium may help in weight control as well. This review summarizes previous literature on the effects and use of dietary minerals on serum lipids, blood pressure and obesity, with specific focus on the effects of calcium. Calcium and magnesium as divalent cations can form insoluble soaps with fatty acids in the intestine and thus prevent the absorption of part of the dietary fat. Decreased absorption of saturated fat leads to reduction in serum cholesterol level via decreased production of VLDL and increased intake of LDL in the liver. Dietary calcium may also bind bile acids, which increases the conversion of cholesterol to bile acids in the liver. Furthermore, calcium appears to enhance the cholesterol-lowering effect of plant sterols. Thus, dietary combination of the mineral nutrients and plant sterols provides a promising novel approach to the modification of cardiovascular risk factors.     

Effect of dietary oils containing different amounts of precursor and derivative fatty acids on prostaglandin E2 synthesis in liver, kidney and lung of rats.

The availability of the fatty acids which are precursors of prostaglandins is affected by dietary intake. We have studied, in particular, the effects of dietary intake of lipids with different amounts of precursor and derivative fatty acids on the synthesis of prostaglandin E2 (PGE2) in rat liver, kidney and lung. Fifteen-month-old rats were fed for 3 months diets containing different amounts of oleic, linoleic, alpha linolenic, gamma linolenic and stearidonic acids. The fatty acid compositions of total phospholipids and prostaglandin E2 levels of liver, kidney and lung were investigated. In the organs studied, the intake of lipids at different amount of precursor/derivative fatty acids caused variations in the fatty acid composition of phospholipids. PGE2 showed different values which did not seem directly affected by tissue availability of arachidonate but by the effect of dietary lipids on the metabolic pool of polyunsaturated fatty acids (PUFAs).     

Role of nuclear receptors in the regulation of gene expression by dietary fatty acids (review)

Long chain fatty acids, derived either from endogenous metabolism or by nutritional sources play significant roles in important biological processes of membrane structure, production of biologically active compounds, and participation in cellular signaling processes. Recently, the structure of dietary fatty acids has become an important issue in human health because ingestion of saturated fats (containing triglycerides composed of saturated fatty acids) is considered harmful, while unsaturated fats are viewed as beneficial. It is important to note that the molecular reason for this dichotomy still remains elusive. Since fatty acids are important players in development of pathology of cardiovascular and endocrine system, understanding the key molecular targets of fatty acids, in particular those that discriminate between saturated and unsaturated fats, is much needed. Recently, insights have been gained on several fatty acid-activated nuclear receptors involved in gene expression. In other words, we can now envision long chain fatty acids as regulators of signal transduction processes and gene regulation, which in turn will dictate their roles in health and disease. In this review, we will discuss fatty acid-mediated regulation of nuclear receptors. We will focus on peroxisome proliferators-activated receptors (PPARs), liver X receptors (LXR), retinoid X receptors (RXRs), and Hepatocyte Nuclear Factor alpha (HNF-4alpha), all of which play pivotal roles in dietary fatty acid-mediated effects. Also, the regulation of gene expression by Conjugated Linoleic Acids (CLA), a family of dienoic fatty acids with a variety of beneficial effects, will be discussed.     

Nuclear receptors, mitochondria and lipid metabolism

Lipid metabolism is a continuum from emulsification and uptake of lipids in the intestine to cellular uptake and transport to compartments such as mitochondria. Whether fats are shuttled into lipid droplets in adipose tissue or oxidized in mitochondria and peroxisomes depends on metabolic substrate availability, energy balance and endocrine signaling of the organism. Several members of the nuclear hormone receptor superfamily are lipid-sensing factors that affect all aspects of lipid metabolism. The physiologic actions of glandular hormones (e.g. thyroid, mineralocorticoid and glucocorticoid), vitamins (e.g. vitamins A and D) and reproductive hormones (e.g. progesterone, estrogen and testosterone) and their cognate receptors are well established. The peroxisome-proliferator activated receptors (PPARs) and liver X receptors (LXRs), acting in concert with PPARgamma Coactivator 1alpha (PGC-1alpha), have been shown to regulate insulin sensitivity and lipid handling. These receptors are the focus of intense pharmacologic studies to expand the armamentarium of small molecule ligands to treat diabetes and the metabolic syndrome (hypertension, insulin resistance, hyperglycemia, dyslipidemia and obesity). Recently, additional partners of PGC-1alpha have moved to the forefront of metabolic research, the estrogen-related receptors (ERRs). Although no endogenous ligands for these receptors have been identified, phenotypic analyses of knockout mouse models demonstrate an important role for these molecules in substrate sensing and handling as well as mitochondrial function.     

Edible nuts and metabolic health

PURPOSE OF REVIEW: This review summarizes evidence for metabolic health benefits of tree nuts and groundnuts (peanuts). While a role for nuts in the dietary management of LDL-cholesterol is well established, it is evident that regular consumption of nuts may also help to counteract other cardiovascular and metabolic risk factors. RECENT FINDINGS: Nuts are not only energy dense foods, they are rich sources of monounsaturated and polyunsaturated fatty acids and other bioactive nutrients with important metabolic effects. Contrary to expectations, epidemiological studies indicate that regular consumption of nuts is unlikely to contribute to obesity or increased risk of diabetes. In fact, it may help to regulate body weight by suppressing appetite and fat absorption. Nut consumption counteracts dyslipidemia and has the capacity to improve circulatory function through the actions of multiple constituents (arginine, polyphenols) on endothelial mechanisms. SUMMARY: Nuts are densely packaged nutrients with wide-ranging cardiovascular and metabolic benefits, which can be readily incorporated in healthy diets. Their potential role in counteracting obesity and the metabolic syndrome warrants further investigation.     

The role of dietary fatty acids in the pathology of metabolic syndrome

Dysfunctional lipid metabolism is a key component in the development of metabolic syndrome, a very frequent condition characterized by dyslipidemia, insulin resistance, abdominal obesity and hypertension, which are related to an elevated risk for type 2 diabetes mellitus. The prevalence of metabolic syndrome is strongly associated with the severity of obesity; its physiopathology is related to both genetics and food intake habits, especially the consumption of a high-caloric, high-fat and high-carbohydrate diet. With the progress of scientific knowledge in the field of nutrigenomics, it was possible to elucidate how the majority of dietary fatty acids influence plasma lipid metabolism and also the genes expression involved in lipolysis and lipogenesis within hepatocytes and adipocytes. The aim of this review is to examine the relevant mechanistic aspects of dietary fatty acids related to blood lipids, adipose tissue metabolism, hepatic fat storage and inflammatory process, all of them closely related to the genesis of metabolic syndrome.     

Thematic Review Series: Bile Acids: Bile acids as regulatory molecules

In the past, bile acids were considered to be just detergent molecules derived from cholesterol in the liver. They were known to be important for the solubilization of cholesterol in the gallbladder and for stimulating the absorption of cholesterol, fat-soluble vitamins, and lipids from the intestines. However, during the last two decades, it has been discovered that bile acids are regulatory molecules. Bile acids have been discovered to activate specific nuclear receptors (farnesoid X receptor, preganane X receptor, and vitamin D receptor), G protein coupled receptor TGR5 (TGR5), and cell signaling pathways (c-jun N-terminal kinase 1/2, AKT, and ERK 1/2) in cells in the liver and gastrointestinal tract. Activation of nuclear receptors and cell signaling pathways alter the expression of numerous genes encoding enzyme/proteins involved in the regulation of bile acid, glucose, fatty acid, lipoprotein synthesis, metabolism, transport, and energy metabolism. They also play a role in the regulation of serum triglyceride levels in humans and rodents. Bile acids appear to function as nutrient signaling molecules primarily during the feed/fast cycle as there is a flux of these molecules returning from the intestines to the liver following a meal. In this review, we will summarize the current knowledge of how bile acids regulate hepatic lipid and glucose metabolism through the activation of specific nuclear receptors and cell signaling pathways.     

Endocrine functions of bile acids

Bile acids (BAs), a group of structurally diverse molecules that are primarily synthesized in the liver from cholesterol, are the chief components of bile. Besides their well-established roles in dietary lipid absorption and cholesterol homeostasis, it has recently emerged that BAs are also signaling molecules, with systemic endocrine functions. BAs activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor TGR5, and activate nuclear hormone receptors such as farnesoid X receptor alpha. Through activation of these diverse signaling pathways, BAs can regulate their own enterohepatic circulation, but also triglyceride, cholesterol, energy, and glucose homeostasis. Thus, BA-controlled signaling pathways are promising novel drug targets to treat common metabolic diseases, such as obesity, type II diabetes, hyperlipidemia, and atherosclerosis.     

Effects of dietary polyunsaturated n-3 fatty acids on dyslipidemia and insulin resistance in rodents and humans. A review

For many years, clinical and animal studies on polyunsaturated n-3 fatty acids (PUFAs), especially those from marine oil, eicosapentaenoic acid (20:5,n-3) and docosahexaenoic acid (22:6,n-3), have reported the impact of their beneficial effects on both health and diseases. Among other things, they regulate lipid levels, cardiovascular and immune functions as well as insulin action. Polyunsaturated fatty acids are vital components of the phospholipids of membrane cells and serve as important mediators of the nuclear events governing the specific gene expression involved in lipid and glucose metabolism and adipogenesis. Besides, dietary n-3 PUFAs seem to play an important protecting role against the adverse symptoms of the Plurimetabolic syndrome. This review highlights some recent advances in the understanding of metabolic and molecular mechanisms concerning the effect of dietary PUFAs (fish oil) and focuses on the prevention and/or improvement of dyslipidemia, insulin resistance, impaired glucose homeostasis, diabetes and obesity in experimental animal models, with some extension to humans.     

Dietary n-3 polyunsaturated fatty acids modify fatty acid composition in hepatic and abdominal adipose tissue of sucrose-induced obese rats

The fatty acid profile of hepatocytes and adipocytes is determined by the composition of the dietary lipids. It remains unclear which fatty acid components contribute to the development or reduction of insulin resistance. The present work examined the fatty acid composition of both tissues in sucrose-induced obese rats receiving fish oil to determine whether the effect of dietary (n-3) polyunsaturated fatty acids (PUFAs) on the reversion of metabolic syndrome in these rats is associated to changes in the fatty acid composition of hepatocyte and adipocyte membrane lipids. Animals with metabolic syndrome were divided into a corn–canola oil diet group and a fish oil diet group, and tissues fatty acids composition were analyzed after 6 weeks of dietary treatment. Fatty acid profiles of the total membrane lipids were modified by the fatty acid composition of the diets fed to rats. N-3 PUFAs levels in animals receiving the fish oil diet plus sucrose in drinking water were significantly higher than in animals under corn–canola oil diets. It is concluded that in sucrose-induced obese rats, consumption of dietary fish oil had beneficial effects on the metabolic syndrome and that such effects would be conditioned by the changes in the n-3 PUFAs composition in hepatic and adipose tissues because they alter membrane properties and modify the type of substrates available for the production of active lipid metabolites acting on insulin resistance and obesity.     

Chronic high-carbohydrate, high-fat feeding in rats induces reversible metabolic, cardiovascular, and liver changes

Age-related physiological changes develop at the same time as the increase in metabolic syndrome in humans after young adulthood. There is a paucity of data in models mimicking chronic diet-induced changes in human middle age and interventions to reverse these changes. This study measured the changes during chronic consumption of a high-carbohydrate (as cornstarch), low-fat (C) diet and a high-carbohydrate (as fructose and sucrose), high-fat (H) diet in rats for 32 wk. C diet feeding induced changes without metabolic syndrome, such as disproportionate increases in total body lean and fat mass, reduced bone mineral content, cardiovascular remodeling with increased systolic blood pressure, left ventricular and arterial stiffness, and increased plasma markers of liver injury. H diet feeding induced visceral adiposity with reduced lean mass, increased lipid infiltration in the skeletal muscle, impaired glucose and insulin tolerance, cardiovascular remodeling, hepatic steatosis, and increased infiltration of inflammatory cells in the heart and the liver. Chia seed supplementation for 24 wk attenuated most structural and functional modifications induced by age or H diet, including increased whole body lean mass and lipid redistribution from the abdominal area, and normalized the chronic low-grade inflammation induced by H diet feeding; these effects may be mediated by increased metabolism of anti-inflammatory n-3 fatty acids from chia seed. These results suggest that chronic H diet feeding for 32 wk mimics the diet-induced cardiovascular and metabolic changes in middle age and that chia seed may serve as an alternative dietary strategy in the management of these changes.