核受体FXR:一种新型代谢调节因子

法尼酯衍生物X受体(farnesoid X receptor,FXR)是一种胆汁酸受体,属于核受体超家族成员。FXR通过调控一系列基因的表达,在胆汁酸、脂质和糖代谢中发挥重要作用,进而有望成为治疗一系列代谢性疾病的药物靶点。本文将就FXR的相关研究进展作一综述。     

核受体的研究进展

核受体是配体依赖性转录因子超家族,与机体生长发育、细胞分化,以及体内许多生理、代谢过程中的基因表达调控密切相关。文中综述了核受体研究的一般概况以及核受体与脂生物学、核受体与肿瘤、核受体与辅调节因子等方面的研究进展。     

Betaine supplementation protects against high-fructose-induced renal injury in rats

High fructose intake causes metabolic syndrome, being an increased risk of chronic kidney disease development in humans and animals. In this study, we examined the influence of betaine on high-fructose-induced renal damage involving renal inflammation, insulin resistance and lipid accumulation in rats and explored its possible mechanisms. Betaine was found to improve high-fructose-induced metabolic syndrome including hyperuricemia, dyslipidemia and insulin resistance in rats with systemic inflammation. Betaine also showed a protection against renal dysfunction and tubular injury with its restoration of the increased glucose transporter 9 and renal-specific transporter in renal brush bolder membrane and the decreased organic anion transporter 1 and adenosine-triphosphate-binding cassette transporter 2 in the renal cortex in this model. These protective effects were relevant to the anti-inflammatory action by inhibiting the production of inflammatory cytokines including interleukin (IL)-1β, IL-18, IL-6 and tumor necrosis factor-α in renal tissue of high-fructose-fed rat, being more likely to suppress renal NOD-like receptor superfamily, pyrin domain containing 3 inflammasome activation than nuclear factor κB activation. Subsequently, betaine with anti-inflammation ameliorated insulin signaling impairment by reducing the up-regulation of suppressor of cytokine signaling 3 and lipid accumulation partly by regulating peroxisome proliferator-activated receptor α/palmityltransferase 1/carnitine/organic cation transporter 2 pathway in kidney of high-fructose-fed rats. These results indicate that the inflammatory inhibition plays a pivotal role in betaine’s improvement of high-fructose-induced renal injury with insulin resistance and lipid accumulation in rats.     

PPAR家族及其与代谢综合征的关系

过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors,PPARs)是配体激活的转录因子核受体超家族成员之一。目前已知有三种亚型：PPARα、-β／δ和-γ。它们在脂肪生成、脂质代谢、胰岛素敏感性、炎症和血压调节中起着关键作用,因而近年来倍受关注。越来越多的研究表明,PPARs与代谢综合征,包括胰岛素抵抗、糖耐量受损、2型糖尿病、肥胖、高脂血症、高血压病、动脉粥样硬化和蛋白尿之间存在因果关系。重要的是,PPARα的激动剂如贝丁酸类降脂药(Fibrate)和PPARγ的激动剂如噻唑烷二酮(Thiazolidinedione,TZD)均已被证实有改善代谢综合征的作用。此外,三种PPAR亚型在2型糖尿病及糖尿病肾病的发展中均有重要作用。不断增加的证据提示,PPARs有可能成为代谢综合征及其相关并发症的潜在治疗靶点。本文将就PPARs的生物学活性、配体选择性和生理学功能作一综述,并对其在代谢综合征发病机制中的作用和PPAR配体对2型糖尿病的治疗效用进行重点讨论。     

核受体FXR调控SHP的机制及FXR-SHP轴在肝脏中作用的研究进展

法尼醇X受体(Farnesoid X Receptor,FXR)属于代谢性核受体,是需配体激活的转录因子,在肝脏胆汁酸、脂质代谢过程,肝脏炎症和肿瘤的发展过程中起着重要的调节作用。小异二聚体伴侣受体(Small Heterodimer Partner,SHP)是核受体超家族中的一个特殊成员,在特异的组织中作为转录调节的共抑制因子,抑制其他多种转录因子的活性,在众多代谢通路中起到了负性调节作用。近年来研究发现,核受体FXR通过对SHP的调控来实现其在肝脏的多种功能。本文着重对FXR调节SHP的机制及FXR-SHP轴在肝脏中作用进行综述。     

Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha

The estrogen-related receptor alpha (ERRalpha) is an orphan member of the superfamily of nuclear hormone receptors expressed in tissues that preferentially metabolize fatty acids. Despite the molecular characterization of ERRalpha and identification of target genes, determination of its physiological function has been hampered by the lack of a natural ligand. To further understand the in vivo function of ERRalpha, we generated and analyzed Estrra-null (ERRalpha-/-) mutant mice. Here we show that ERRalpha-/- mice are viable, fertile and display no gross anatomical alterations, with the exception of reduced body weight and peripheral fat deposits. No significant changes in food consumption and energy expenditure or serum biochemistry parameters were observed in the mutant animals. However, the mutant animals are resistant to a high-fat diet-induced obesity. Importantly, DNA microarray analysis of gene expression in adipose tissue demonstrates altered regulation of several enzymes involved in lipid, eicosanoid, and steroid synthesis, suggesting that the loss of ERRalpha might interfere with other nuclear receptor signaling pathways. In addition, the microarray study shows alteration in the expression of genes regulating adipogenesis as well as energy metabolism. In agreement with these findings, metabolic studies showed reduced lipogenesis in adipose tissues. This study suggests that ERRalpha functions as a metabolic regulator and that the ERRalpha-/- mice provide a novel model for the investigation of metabolic regulation by nuclear receptors.     

Design, synthesis, and structure-activity relationship of podocarpic acid amides as liver X receptor agonists for potential treatment of atherosclerosis

A series of podocarpic acid amides were identified as potent agonists for Liver X receptor alpha and beta subtypes, which are members of a nuclear hormone receptor superfamily that are involved in the regulation of a variety of metabolic pathways including cholesterol metabolism. We recently reported podocarpic acid anhydride and imide dimers as potent LXR agonists. Through parallel organic synthesis, we rapidly identified a series of new podocarpate leads with stable structures exemplified by adamantyl- and phenylcyclohexylmethyl-podocarpic acid amides (14 and 18). Compound 18 exhibited LXRalpha/beta 50/20 nM (binding affinity) and 33.7/35.3-fold receptor inductions. Synthesis, SAR, and biological activities of new podocarpate analogs are 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.     

FXR signaling in metabolic disease

Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, has been shown to be important in controlling numerous metabolic pathways; these include roles in maintaining bile acid, lipid and glucose homeostasis, in preventing intestinal bacterial infection and gallstone formation and in modulating liver regeneration and tumorigenesis. The accumulating data suggest that FXR may be a pharmaceutical target for the treatment of certain metabolic diseases.     

Major Facilitator Superfamily Domain-Containing Protein 2a (MFSD2A) Has Roles in Body Growth,Motor Function,and Lipid Metabolism

The metabolic adaptations to fasting in the liver are largely controlled by the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARα), where PPARα upregulates genes encoding the biochemical pathway for β-oxidation of fatty acids and ketogenesis. As part of an effort to identify and characterize nutritionally regulated genes that play physiological roles in the adaptation to fasting, we identified Major facilitator superfamily domain-containing protein 2a (Mfsd2a) as a fasting-induced gene regulated by both PPARα and glucagon signaling in the liver. MFSD2A is a cell-surface protein homologous to bacterial sodium-melibiose transporters. Hepatic expression and turnover of MFSD2A is acutely regulated by fasting/refeeding, but expression in the brain is constitutive. Relative to wildtype mice, gene-targeted Mfsd2a knockout mice are smaller, leaner, and have decreased serum, liver and brown adipose triglycerides. Mfsd2a knockout mice have normal liver lipid metabolism but increased whole body energy expenditure, likely due to increased β-oxidation in brown adipose tissue and significantly increased voluntary movement, but surprisingly exhibited a form of ataxia. Together, these results indicate that MFSD2A is a nutritionally regulated gene that plays myriad roles in body growth and development, motor function, and lipid metabolism. Moreover, these data suggest that the ligand(s) that are transported by MFSD2A play important roles in these physiological processes and await future identification.     

Nuclear receptors in renal disease

Diabetes is the leading cause of end-stage renal disease in developed countries. In spite of excellent glucose and blood pressure control, including administration of angiotensin converting enzyme inhibitors and/or angiotensin II receptor blockers, diabetic nephropathy still develops and progresses. The development of additional protective therapeutic interventions is, therefore, a major priority. Nuclear hormone receptors regulate carbohydrate metabolism, lipid metabolism, the immune response, and inflammation. These receptors also modulate the development of fibrosis. As a result of their diverse biological effects, nuclear hormone receptors have become major pharmaceutical targets for the treatment of metabolic diseases. The increasing prevalence of diabetic nephropathy has led intense investigation into the role that nuclear hormone receptors may have in slowing or preventing the progression of renal disease. This role of nuclear hormone receptors would be associated with improvements in metabolism, the immune response, and inflammation. Several nuclear receptor activating ligands (agonists) have been shown to have a renal protective effect in the context of diabetic nephropathy. This review will discuss the evidence regarding the beneficial effects of the activation of several nuclear, especially the vitamin D receptor (VDR), farnesoid X receptor (FXR), and peroxisome-proliferator-associated receptors (PPARs) in preventing the progression of diabetic nephropathy and describe how the discovery and development of compounds that modulate the activity of nuclear hormone receptors may provide potential additional therapeutic approaches in the management of diabetic nephropathy. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.     

PPARγ在肿瘤中的双重作用

过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptor γ,PPARγ)是一种配体依赖的核转录因子,属于Ⅱ型核激素受体超家族成员.以前的研究主要集中于PPARy在调控脂质代谢、糖代谢、免疫炎症、细胞增殖和分化等方面的作用.随着研究的深入,PPARγ在肿瘤中发挥...     

Nuclear receptor signalling in dendritic cells connects lipids, the genome and immune function

Dendritic cells (DCs) are sentinels of the immune system and represent a heterogeneous cell population. The existence of distinct DC subsets is due to their inherent plasticity and to the changing microenvironment modulating their immunological properties. Numerous signalling pathways have impacts on DCs. It appears that besides cytokines/chemokines, lipid mediators also have profound effects on the immunogenicity of DCs. Some of these lipid mediators exert an effect through nuclear hormone receptors. Interestingly, more recent findings suggest that DCs are able to convert precursors to active hormones, ligands for nuclear receptors. Some of these DC-derived lipids, in particular retinoic acid (RA), have a central function in shaping T-cell development and effector functions. In this review, we summarize and highlight the function of a set of nuclear receptors (PPARgamma, RA receptor, vitamin D receptor and glucocorticoid receptor) in DC biology. Defining the contribution of nuclear hormone receptor signalling in DCs can help one to understand the regulatory logic of lipid signalling and allow the exploitation of their potential for therapeutic intervention in various immunological diseases.