FGF21代谢调节机制的研究进展

代谢综合征在全世界广泛流行，我国代谢综合征的发病率已达24.2%。代谢综合征是糖尿病和心血管疾病发病的危险因素。成纤维细胞生长因子21(fibroblast growth factor 21,FGF21)是一种代谢信号调节蛋白，外源性FGF21类似物具有降低血糖、血脂和体重等多种药理作用，但FGF21调节代谢的机制目前仍不明确，可能涉及脂联素依赖途径、非脂联素依赖途径和大脑中枢调节途径等。临床研究发现，高水平的FGF21与代谢综合征的发生、发展和不良预后密切相关，存在“FGF21抵抗”。本文旨在概述FGF21代谢调节机制的最新研究进展，以期为代谢性疾病的临床诊疗和研究提供新思路。     

成纤维细胞生长因子21的研究进展*

成纤维细胞生长因子21（fibroblast growth factor 21,FGF21）是一种主要的脂肪代谢调节因子,主要在肝脏中表达;FGF21有助于肝脏的脂肪代谢以及生酮反应,可以促进脂肪细胞摄取葡萄糖,促进胰岛素分泌,延缓肿瘤的发展等功能。近年来研究过程中发现,FGF21可以用于糖尿病和降血脂等其他代谢疾病治疗。主要对FGF21的特点,作用机理及其分子机制进行了概括,并对FGF21在糖尿病治疗和降血脂方面的研究进行了综述。     

脂滴包被蛋白2在动脉粥样硬化中的作用

动脉粥样硬化性心血管疾病严重威胁着人类生命健康,其中脂质代谢异常和炎症反应是其重要的发病机制。脂滴是细胞内储存脂质的一种亚细胞器,其表面存在多种脂滴包被蛋白,参与调控脂质动态平衡。脂滴包被蛋白2(Plin2)作为脂滴包被蛋白的一种,在脂质代谢的调节、脂肪酸的氧化及炎症反应等多种生理功能中发挥重要作用。近年来,越来越多的研究发现Plin2在动脉粥样硬化的发生发展中扮演着重要的角色。因此,本文主要综述Plin2在胆固醇代谢、脂质合成、自噬和炎症反应等过程中发挥的作用,进一步阐述其与动脉粥样硬化之间的关系。     

成纤维细胞生长因子21对糖脂代谢调控的研究进展

成纤维细胞生长因子21(FGF21)是成纤维细胞生长因子(FGF)家族中的一员。由于它在改善能量代谢方面的积极作用,近年来获得了广泛的关注。FGF21可作用于多个组织参与调控糖脂代谢:减轻体重,改善肥胖、糖尿病等病理情况下的高血糖及高血脂;此外,FGF21在调节饥饿等特殊生理状态的能量代谢中也起着重要的作用。本文就FGF21调控糖脂代谢的研究进展作一综述,以便更好地理解其作用机制,为慢性代谢性疾病的防治提供依据。     

运动调控FGF21在改善肥胖相关代谢性疾病中的作用

肥胖是糖尿病、脂肪肝、心血管疾病等慢性代谢性疾病发生发展的重要风险因素。运动可以改善肥胖,对相关代谢性疾病的预防与康复具有积极作用。成纤维细胞生长因子21 (fibroblast growth factor 21,FGF21)是一种对机体能量稳态、糖脂代谢有积极调控作用的内分泌因子,是代谢性疾病预防和治疗的有效靶点之一。FGF21抵抗是机体对FGF21反应性减弱的现象,表现为靶组织生物学效应降低,机体FGF21代偿性合成增加。这可能是由FGF21受体(fibroblast growth factor receptors,FGFRs)和β-klotho蛋白(β-klotho,KLB)表达减少或敏感性降低所致。肥胖患者常出现FGF21抵抗,改善FGF21抵抗是治疗肥胖及相关代谢性疾病的新思路。运动不仅可以增加部分组织FGF21表达量,还可以刺激FGFRs与KLB的表达来敏化FGF21的作用,改善FGF21抵抗。     

动脉粥样硬化中胆固醇逆向转运的研究进展

胆固醇逆向转运(reverse cholesterol transport,RCT)是指胆固醇从外周组织细胞流出,通过高密度脂蛋白转运至肝脏进行代谢转变的过程,是维持细胞脂质稳态的重要机制。RCT相关基因的功能障碍是动脉粥样硬化脂质沉积、慢性炎症和泡沫细胞形成的主要病因,已成为抗动脉粥样硬化的主要靶点。该文就近年来关于胆固醇逆向转运的调节和定量分析在动脉粥样硬化中的最新研究进展作一综述。     

FGF21与代谢性疾病防治及其运动干预

成纤维细胞生长因子21(fibroblast growth factor 21, FGF21)属于成纤维细胞生长因子家族FGF19(fibroblast growth factor 19, FGF19)的亚型,不具有促成纤维细胞生长活性,且不与肝素特异性结合,是一种调节机体代谢的分泌型蛋白。在骨骼肌、肾脏、心脏以及血管和脂肪组织中 fgf21 表达比肝脏中高约7~10倍。FGF21可靶向脑、心脏、骨骼肌以及肾脏和肠等多种组织器官发挥作用。近来证实,FGF21已广泛应用于肝脂、糖脂代谢以及心血管疾病等代谢性疾病的预防与康复,可能成为代谢性疾病预防和康复的有效靶点之一。急性运动后骨骼肌FGF21表达显著升高,耐力运动可改善FGF21对肝脏脂肪调节的抵抗,有氧运动和抗阻运动可显著提高肝脏FGF21表达水平,单次急性运动后小鼠血清FGF21水平呈上升趋势。表明运动可显著提高循环和靶器官FGF21水平。积极开展运动介导的FGF21表达与肝脂、糖脂代谢紊乱及心血管等疾病康复研究,将为代谢性疾病预防与康复及其相关药物筛选提供新思路和新靶点。     

转基因小鼠在脂质代谢研究中的应用

转基因小鼠在脂质代谢研究中的应用汝昆综述琦祖和校（中国医学科学院基础医学研究所医学分子生物学国家重点实验室,北京）动脉粥样硬化是一种严重危害人类身体健康的多发性疾病,该病与脂质代谢紊乱有非常密切的关系。本文综述了近年来转基因小鼠技术在脂质代谢研究中的...     

成纤维细胞生长因子21:参与代谢调节的细胞因子

成纤维细胞生长因子21(FGF21)作为新近发现的内源性调节物质代谢因子,可由人体两大内分泌器官肝脏及骨骼肌分泌,其在调节代谢性疾病方面的生理作用近年来被医学界密切关注.大量研究发现FGF21可增加能量消耗、降低血浆与肝脏甘油三脂及低密度脂蛋白水平;调节葡萄糖代谢,发挥增强脂肪细胞摄取葡萄糖能力、降低血糖及抑制胰高血糖素分泌的作用.在临床2型糖尿病及非酒精性脂肪肝患者血浆中FGF21水平与对照组的显著差异具有统计学意义,且在控制其它因素后,其与病情的预后显著相关.而对于心血管病患者,FGF21可能通过其各项生理作用,拮抗心肌细胞凋亡及增强心肌抗氧化能力,一定程度上延缓心血管疾病的发生发展,但FGF21上述调节代谢相关性疾病的生理作用机制及途径目前尚不完全明确.本文简述FGF21的生物学特性及在代谢性疾病中的研究进展.     

成纤维细胞生长因子21通过诱导自噬在心血管疾病中发挥保护作用

成纤维细胞生长因子21 (fibroblast growth factor 21, FGF21)是成纤维细胞生长因子家族中一个具有内分泌性质的生长因子。既往报道显示,FGF21参与能量代谢的调节过程,并在冠状动脉粥样硬化性心脏病、糖尿病、非酒精性脂肪肝病等心血管相关疾病中具有保护作用。新近研究发现,FGF21在多种组织和器官中可诱导自噬,而自噬参与了包括血管钙化、动脉粥样硬化、心肌缺血/再灌注损伤在内的多种心血管疾病的病理过程。因此,有学者推测FGF21可能通过调控自噬在多种心血管相关疾病中发挥保护作用。本文就FGF21通过诱导自噬在心血管疾病中发挥保护作用的相关研究进展作一综述。     

Rush to the fire: FGF21 extinguishes metabolic stress,metaflammation and tissue damage

FGF21 is a master regulator of homeostasis of local and systemic lipid, glucose and energy metabolism. Since its discovery a decade ago, significant progress has been made in understanding the basic molecular, cellular and physiological mechanisms underlying its metabolic roles, and characterizing its beneficial pharmacological activities and possible pathological roles in obesity, diabetes, dyslipidemia, fatty liver disease and their collateral complications and tissue damage. Under basal or normal conditions, FGF21 appears to play a dispensable role in metabolism. However, in response to a variety of cellular and metabolic stress, FGF21 is significantly upregulated to serve as a potent catabolic factor leading to the clearance of excessive lipids and glucose, and therefore, antagonizes metabolic and energy imbalance in a negative fashion. Furthermore, FGF21 treatment ameliorates tissue damage resulted from the harmful effects of metabolic abnormalities, which often ensue an oxidative, pro-inflammatory, inflammatory and/or immune stress state, the so-called metaflammation. Most notably, studies focusing on the liver, pancreas, cardio-vasculature and kidney have revealed its significant protective effects against the structural and functional damages induced by the obese, diabetic or other abnormal metabolic conditions. In this review, we will summarize the current progress on the roles of FGF21 against metaflammation and metabolic tissue damage.     

FGF21 induces autophagy‐mediated cholesterol efflux to inhibit atherogenesis via RACK1 up‐regulation

Fibroblast growth factor 21 (FGF21) acts as an anti‐atherosclerotic agent. However, the specific mechanisms governing this regulatory activity are unclear. Autophagy is a highly conserved cell stress response which regulates atherosclerosis (AS) by reducing lipid droplet degradation in foam cells. We sought to assess whether FGF21 could inhibit AS by regulating cholesterol metabolism in foam cells via autophagy and to elucidate the underlying molecular mechanisms. In this study, ApoE^?/? mice were fed a high‐fat diet (HFD) with or without FGF21 and FGF21 + 3‐Methyladenine (3MA) for 12 weeks. Our results showed that FGF21 inhibited AS in HFD‐fed ApoE^?/? mice, which was reversed by 3MA treatment. Moreover, FGF21 increased plaque RACK1 and autophagy‐related protein (LC3 and beclin‐1) expression in ApoE^?/? mice, thus preventing AS. However, these proteins were inhibited by LV‐RACK1 shRNA injection. Foam cell development is a crucial determinant of AS, and cholesterol efflux from foam cells represents an important defensive measure of AS. In this study, foam cells were treated with FGF21 for 24 hours after a pre‐treatment with 3MA, ATG5 siRNA or RACK1 siRNA. Our results indicated that FGF21‐induced autophagy promoted cholesterol efflux to reduce cholesterol accumulation in foam cells by up‐regulating RACK1 expression. Interestingly, immunoprecipitation results showed that RACK1 was able to activate AMPK and interact with ATG5. Taken together, our results indicated that FGF21 induces autophagy to promote cholesterol efflux and reduce cholesterol accumulation in foam cells through RACK1‐mediated AMPK activation and ATG5 interaction. These results provided new insights into the molecular mechanisms of FGF21 in the treatment of AS.     

Dual actions of fibroblast growth factor 19 on lipid metabolism

Elevated triglyceride (TG) and cholesterol levels are risk factors for cardiovascular disease and are often associated with diabetes and metabolic syndrome. Recent reports suggest that fibroblast growth factor (FGF)19 and FGF21 can dramatically improve metabolic dysfunction, including hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. Due to their similar receptor specificities and co-receptor requirements, FGF19 and FGF21 share many common properties and have been thought to be interchangeable in metabolic regulation. Here we directly compared how pharmacological administration of recombinant FGF19 or FGF21 proteins affect metabolism in B6.V-Lep^ob/J leptin-deficient mice. FGF19 and FGF21 equally improved glucose parameters; however, we observed increased serum TG and cholesterol levels after treatment with FGF19 but not with FGF21. Increases in serum TGs were also observed after a 4-day treatment with FGF19 in C57BL6/J mice on a high-fat diet. This is in contrast to many literature reports that showed significant improvements in hyperlipidemia after chronic treatment with FGF19 or FGF21 in high-fat diet models. We propose that FGF19 has lipid-raising and lipid-lowering actions mediated through different FGF receptors and target tissues, and the results described here provide a potential mechanism that may explain the inconsistency in the reported effects of FGF19 on lipid metabolism.     

βKlotho Is Required for Fibroblast Growth Factor 21 Effects on Growth and Metabolism

Fibroblast growth factor 21 (FGF21) is a fasting-induced hepatokine that has potent pharmacologic effects in mice, which include improving insulin sensitivity and blunting growth. The single-transmembrane protein βKlotho functions as a coreceptor for FGF21 in?vitro. To determine if βKlotho is required for FGF21 action in?vivo, we generated whole-body and adipose tissue-selective βKlotho-knockout mice. All of the effects of FGF21 on growth and metabolism were lost in whole-body βKlotho-knockout mice. Selective elimination of βKlotho in adipose tissue blocked the acute insulin-sensitizing effects of FGF21. Taken together, these data demonstrate that βKlotho is essential for FGF21 activity and that βKlotho in adipose tissue contributes to the beneficial metabolic actions of FGF21.     

The emerging role of fibroblast growth factor 21 in diabetic nephropathy

Diabetic nephropathy (DN), an important cause of end-stage renal diseases, brings about great social and economic burden. Due to the variable pathological changes and clinical course, the prognosis of DN is very difficult to predict. DN is also usually associated with enhanced genomic damage and cellular injury. Fibroblast growth factor 21 (FGF21), a nutritionally regulated hormone secreted mainly by the liver, plays a critical role in metabolism. Administration of FGF21 decreases blood glucose, triglyceride, and cholesterol levels, and improves insulin sensitivity, which is closely associated with the development and progression of glomerular diseases. In addition, FGF21 level was associated with renal function. However, the precise role of FGF21 in DN remains unclear. This review will give a comprehensive understanding of the underlying role of FGF21 and its possible interaction with other molecules in DN.     

Fibroblast growth factor 21 alleviates acute pancreatitis via activation of the Sirt1‐autophagy signalling pathway

Fibroblast growth factor 21 (FGF21), a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity, alleviates the process of acute pancreatitis (AP). However, its mechanism remains elusive. The pathological and physiological characteristics of FGF21 are observed in both patients with AP and cerulein‐induced AP models, and the mechanisms of FGF21 in response to AP are investigated by evaluating the impact of autophagy in FGF21‐treated mice and cultured pancreatic cells. Circulating levels of FGF21 significantly increase in both AP patients and cerulein‐induced AP mice, which is accompanied by the change of pathology in pancreatic injury. Replenishment of FGF21 distinctly reverses cerulein‐induced pancreatic injury and improves cerulein‐induced autophagy damage in vivo and in vitro. Mechanically, FGF21 acts on pancreatic acinar cells to up‐regulate Sirtuin‐1 (Sirt1) expression, which in turn repairs impaired autophagy and removes damaged organs. In addition, blockage of Sirt1 accelerates cerulein‐induced pancreatic injury and weakens the regulative effect in FGF21‐activated autophagy in mice. These results showed that FGF21 protects against cerulein‐induced AP by activation of Sirtuin‐1‐autophagy axis.