Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR

Nuclear receptors are integrators of hormonal and nutritional signals, mediating changes to metabolic pathways within the body. Given that modulation of lipid and glucose metabolism has been linked to diseases including type 2 diabetes, obesity and atherosclerosis, a greater understanding of pathways that regulate metabolism in physiology and disease is crucial. The liver X receptors (LXRs) and the farnesoid X receptors (FXRs) are activated by oxysterols and bile acids, respectively. Mounting evidence indicates that these nuclear receptors have essential roles, not only in the regulation of cholesterol and bile acid metabolism but also in the integration of sterol, fatty acid and glucose metabolism.     

Cellular lipid binding proteins as facilitators and regulators of lipid metabolism

Evidence is accumulating that cellular lipid binding proteins are playing central roles in cellular lipid uptake and metabolism. Membrane-associated fatty acid-binding proteins putatively function in protein-mediated transmembrane transport of fatty acids, likely coexisting with passive diffusional uptake. The intracellular trafficking of fatty acids, bile acids, and other lipid ligands, may involve their interaction with specific membrane or protein targets, which are unique properties of some but not of all cytoplasmic lipid binding proteins. Recent studies indicate that these proteins not only facilitate but also regulate cellular lipid utilization. For instance, muscle fatty acid uptake is subject to short-term regulation by translocation of fatty acid translocase (FAT)/CD36 from intracellular storage sites to the plasma membrane, and liver-type cytoplasmic fatty acid-binding protein (L-FABP_c) functions in long-term, ligand-induced regulation of gene expression by directly interacting with nuclear receptors. Therefore, the properties of the lipid-protein complex, rather than those of the lipid ligand itself, determine the fate of the ligand in the cell. Finally, there are an increasing number of reports that deficiencies or altered functioning of both membrane-associated and cytoplasmic lipid binding proteins are associated with disease states, such as obesity, diabetes and atherosclerosis. In conclusion, because of their central role in the regulation of lipid metabolism, cellular lipid binding proteins are promising targets for the treatment of diseases resulting from or characterised by disturbances in lipid metabolism, such as atherosclerosis, hyperlipidemia, and insulin resistance.     

Effect of docosahexaenoic acid on interleukin-2 receptor signaling pathway in lipid rafts

PUFAs have been shown to mediate immune re-sponse especially the functions of T cells[1]. Recent researches have demonstrated that PUFAs can in-crease membrane fluidity and modify the functions of membrane receptors and enzymes in T cell membra-ne[2,3]. M…     

Effect of docosahexaenoic acid on interleukin-2 receptor signaling pathway in lipid rafts

Recent studies have shown that polyunsaturated fatty acids (PUFA) regulated the functions of membrane receptors in T cells and suppressed T cell-mediated immune responses. But the molecular mechanisms of immune regulation are not yet elucidated. Lipid rafts are plasma membrane microdomains, in which many receptors localized. The purpose of this study was to investigate the effect of DHA on IL-2R signaling pathway in lipid rafts. We isolated lipid rafts by discontinuous sucrose density gradient ultracentrifugation, and found that DHA could change the composition of lipid rafts and alter the distribution of key molecules of IL-2R signaling pathway, which transferred from lipid rafts to detergent-soluble membrane fractions. These results revealed that DHA treatment increased the proportion of polyunsaturated fatty acids especially n−3 polyunsaturated fatty acids in lipid rafts and changed the lipid environment of membrane microdomains in T cells. Compared with controls, DHA changed the localization of IL-2R, STAT5a and STAT5b in lipid rafts and suppressed the expression of JAK1, JAK3 and tyrosine phosphotyrosine in soluble membrane fractions. Summarily, this study concluded the effects of DHA on IL-2R signaling pathway in lipid rafts and explained the regulation of PUFAs in T cell-mediated immune responses.     

Effects of short chain fatty acid producing bacteria on epigenetic regulation of FFAR3 in type 2 diabetes and obesity

The human gut microbiota and microbial influences on lipid and glucose metabolism, satiety, and chronic low-grade inflammation are known to be involved in metabolic syndrome. Fermentation end products, especially short chain fatty acids, are believed to engage the epigenetic regulation of inflammatory reactions via FFARs (free fatty acid receptor) and other short chain fatty acid receptors.     

LXR is crucial in lipid metabolism

Liver X receptors (LXRalpha and LXRbeta) are members of the nuclear receptor superfamily and are activated by oxysterols and intermediates in the cholesterol synthetic pathway. The pivotal role of LXRs in the metabolic conversion of cholesterol to bile acids is well established. Analysis of gene expression in LXRalpha and LXRbeta deficient mice have confirmed that LXR regulates a number of target genes involved in both cholesterol and fatty acid metabolism in liver, macrophages and intestine. The observation that LXRalpha is responsive to fatty acids and is expressed in metabolic tissues suggests that it also plays a general role in lipid metabolism. Adipose tissue is the main storage site for fat in the body and plays a crucial role in overall lipid handling. Both LXRalpha and LXRbeta are expressed and activated by endogenous and synthetic ligands, which lead to lipid accumulation into adipocytes. This indicates an important regulatory role of LXR in several metabolic signaling pathways in the adipose tissue, such as glucose uptake and de novo fatty acid synthesis. Here, we review recent studies that provide new insights into the mechanisms by which LXRs act to influence fatty acid synthesis in liver and adipose tissue.     

过氧化物酶体增殖物激活受体α的研究进展

过氧化物酶体增殖物激活受体（Peroxisome proliferator activated receptors,PPARs）作为核受体超家族的一员,其作用广泛,可调节脂肪细胞因子表达、抑制炎症因子、改善胰岛素抵抗等。PPARs有三种亚型,分别是：PPARα、PPARβ／δ和PPARγ。其中PPARα是PPARs最主要的亚型,主要分布在肝脏中。PPARα由不饱和脂肪酸或贝特类降脂药物等配体活化后形成异二聚体,调控靶基因的表达,发挥生物学功能。PPARα参与调节肝脏脂质吸收、脂肪酸氧化、酮体生成、胆固醇代谢等脂代谢过程,以及糖代谢、炎症反应和细胞增殖等,与脂肪性肝病、肝脏炎症反应、乙肝病毒复制和肝癌等肝脏疾病密切相关。本文对PPARα的结构、作用机制、生物学功能及其与肝脏疾病的关系进行综述。PPARα作为肝脏疾病一个新的治疗靶点,阐明其与肝脏疾病发生机制之间的关系,有助于为肝脏疾病的治疗提供新的途径。     

Peroxisome proliferator-activated receptor alpha in metabolic disease, inflammation, atherosclerosis and aging.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors which are activated by fatty acids and derivatives. The PPAR alpha form has been shown to mediate the action of the hypolipidemic drugs of the fibrate class on lipid and lipoprotein metabolism. PPAR alpha activators furthermore improve glucose homeostasis and influence body weight and energy homeostasis. It is likely that these actions of PPAR alpha activators on lipid, glucose and energy metabolism are, at least in part, due to the increase of hepatic fatty acid beta-oxidation resulting in an enhanced fatty acid flux and degradation in the liver. Moreover, PPARs are expressed in different immunological and vascular wall cell types where they exert anti-inflammatory and proapoptotic activities. The observation that these receptors are also expressed in atherosclerotic lesions suggests a role in atherogenesis. Finally, PPAR alpha activators correct age-related dysregulations in redox balance. Taken together, these data indicate a modulatory role for PPAR alpha in the pathogenesis of age-related disorders, such as dyslipidemia, insulin resistance and chronic inflammation, predisposing to atherosclerosis.     

Isolation and characterization of unsaturated fatty acids as natural ligands for the retinoid-X receptor

The retinoid-X receptor (RXR) is a ligand activated nuclear receptor that is the heterodimer partner for many class II nuclear receptors. Previously identified natural ligands for this receptor include 9-cis retinoic acid (9cRA), docosahexaenoic acid, and phytanic acid. Our studies were performed to determine if there are any unidentified, physiologically important RXR ligands. Agonists for RXR were purified from rat heart and testes lipid extracts with the use of a cell-based reporter assay to monitor RXR activation. Purified active fractions contained a variety of unsaturated fatty acids and components were quantified by gas-liquid chromatography of derivatized samples. The corresponding fatty acid standards elicited a similar response in the reporter cell assay. Competition binding analysis revealed that the active fatty acids compete with [3H]9cRA for binding to RXR. Non-esterified fatty acids were analyzed from lipid extracts of isolated heart and testes nuclei and endogenous concentrations were found to be within the range of their determined binding affinities. Our studies reveal tissue dependent profiles of RXR agonists and support the idea of unsaturated fatty acids as physiological ligands of RXR.     

Alterations of peroxisome proliferator-activated receptor delta activity affect fatty acid-controlled adipose differentiation

Fatty acids have been postulated to regulate adaptation of adipose mass to nutritional changes by controlling expression of genes implicated in lipid metabolism via activation of nuclear receptors. Ectopic expression of the nuclear receptors PPARgamma or PPARdelta promotes adipogenesis in fibroblastic cells exposed to thiazolidinediones or long-chain fatty acids. To investigate the role of PPARdelta in fatty acid regulation of gene expression and adipogenesis in a preadipose cellular context, we studied the effects of overexpressing the native receptor or the dominant-negative PPARdelta mutant in Ob1771 and 3T3-F442A cells. Overexpression of PPARdelta enhanced fatty acid induction of the adipose-related genes for fatty acid translocase, adipocyte lipid binding protein, and PPARgamma and fatty acid effects on terminal differentiation. A transactivation-deficient form of PPARdelta mutated in the AF2 domain severely reduced these effects. Findings are similar in Ob1771 or 3T3-F442A preadipose cells. These data demonstrate that PPARdelta plays a central role in fatty acid-controlled differentiation of preadipose cells. Furthermore, they suggest that modulation of PPARdelta expression or activity could affect adaptive responses of white adipose tissue to nutritional changes.     

Cardiac-specific knock-out of lipoprotein lipase alters plasma lipoprotein triglyceride metabolism and cardiac gene expression

Fatty acids are the primary energy source for the heart. The heart acquires fatty acids associated with albumin or derived from lipoprotein lipase (LpL)-mediated hydrolysis of lipoprotein triglyceride (TG). We generated heart-specific LpL knock-out mice (hLpL0) to determine whether cardiac LpL modulates the actions of peroxisome proliferator-activated receptors and affects whole body lipid metabolism. Male hLpL0 mice had significantly elevated plasma TG levels and decreased clearance of postprandial lipids despite normal postheparin plasma LpL activity. Very large density lipoprotein-TG uptake was decreased by 72% in hLpL0 hearts. However, heart uptake of albumin-bound free fatty acids was not altered. Northern blot analysis revealed a decrease in the expression of peroxisome proliferator-activated receptor alpha-response genes involved in fatty acid beta-oxidation. Surprisingly, the expression of glucose transporters 1 and 4 and insulin receptor substrate 2 was increased and that of pyruvate dehydrogenase kinase 4 and insulin receptor substrate 1 was reduced. Basal glucose uptake was increased markedly in hLpL0 hearts. Thus, the loss of LpL in the heart leads to defective plasma metabolism of TG. Moreover, fatty acids derived from lipoprotein TG and not just albumin-associated fatty acids are important for cardiac lipid metabolism and gene regulation.     

Intracellular lipid binding proteins and nuclear receptors involved in branched-chain fatty acid signaling

Branched-chain fatty acids are potent regulators of gene expression. Among them are the vitamin A-derived retinoic acids, which are involved in cell growth and differentiation, and the chlorophyll-derived phytol metabolites such as phytanic and pristanic acids, which affect catabolic lipid metabolism. Gene expression regulated by these signaling molecules is mediated by two protein families. These are, on the one hand, the intracellular lipid binding proteins, i.e. cellular retinoic acid binding protein and liver-type fatty acid binding protein, which are responsible for ligand-transport to the nucleus. On the other hand are the ligand-activated nuclear receptors, i.e. the retinoic acid receptors for retinoic acids and the peroxisome proliferator-activated receptors for the phytol metabolites. In this review, we discuss the cross-talk between the two protein families and how this cross-talk contributes to targeted signaling with branched-chain fatty acids.     

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.     

The regulation of fatty acid metabolism and other lipid compounds in ruminant animals

The review deals with peculiarities of molecular mechanisms of metabolism regulation of fatty acids and other lipid components in preruminant and ruminant animals (i.e. before and after formation of the functioning of the mixed microbial population in the rumen). A characteristic of possible biosynthesis regulation processes, transformation, transport, utilization and catabolism of fatty acids with different molecular masses and peculiarities and of triacylglycerols and other lipid substances in the liver compartments, skeletal and heart muscle cells has been shown. Peculiarities of intracellular changes in metabolism of fatty acids and apolipoprotein B in the liver of neonatal calves under development of alimentary enteropathology have been considered. Main factors in the mechanism of regulation of intracellular metabolism of fatty acids and lipid substances have been defined.