奥美沙坦减轻高脂饮食诱导的非酒精性脂肪肝病的机制研究

目的探讨奥美沙坦对于高脂诱导的非酒精性脂肪肝病（NAFLD）的影响及可能机制。方法健康雄性8周龄C57BL／6小鼠24只随机分为高脂组（n=16）和正常饮食组（n=8）,高脂组小鼠高脂饮食（60％的脂肪）12w后再随机分为高脂饮食对照组（n=8）、高脂饮食治疗组（n=8）。高脂饮食治疗组小鼠给予0．75mg／kg／d的奥美沙坦灌胃8w,灌胃结束后处理小鼠,留取空腹血样本检测AST和ALT。肝组织冰冻切片行油红O染色观察脂肪变;石蜡切片行HE和F4／80免疫组化染色观察肝脏炎症变化;实时荧光定量PCR检测肝脏TNF-α和IL-6mRNA的表达水平;WesternBlot检测肝组织中IκB-α、p-IκBa、NF—κB信号通路的活化。结果奥美沙坦显著抑制了高脂诱导的NAFLD脂肪变性,并明显改善肝功能。实时荧光定量PCR结果表明奥美沙坦能显著降低肝脏组织中TNF-α和IL-6mRNA表达水平（P〈0．05）;Western Blot结果显示奥美沙坦显著抑制肝脏NF-κB信号通路活化。结论奥美沙坦显著抑制NAFLD小鼠肝脏炎性病变而保护肝功能,其机制与抑制NF-κB信号通路活化以及降低肝脏TNF-α和IL-6mRNA水平有关。     

Bile acids,FGF15/19 and liver regeneration: From mechanisms to clinical applications

The liver has an extraordinary regenerative capacity rapidly triggered upon injury or resection. This response is intrinsically adjusted in its initiation and termination, a property termed the “hepatostat”. Several molecules have been involved in liver regeneration, and among them bile acids may play a central role. Intrahepatic levels of bile acids rapidly increase after resection. Through the activation of farnesoid X receptor (FXR), bile acids regulate their hepatic metabolism and also promote hepatocellular proliferation. FXR is also expressed in enterocytes, where bile acids stimulate the expression of fibroblast growth factor 15/19 (FGF15/19), which is released to the portal blood. Through the activation of FGFR4 on hepatocytes FGF15/19 regulates bile acids synthesis and finely tunes liver regeneration as part of the “hepatostat”. Here we review the experimental evidences supporting the relevance of the FXR-FGF15/19-FGFR4 axis in liver regeneration and discuss potential therapeutic applications of FGF15/19 in the prevention of liver failure. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.     

FGF21 mediates alcohol-induced adipose tissue lipolysis by activation of systemic release of catecholamine in mice

Alcohol consumption leads to adipose tissue lipoatrophy and mobilization of FFAs, which contributes to hepatic fat accumulation in alcoholic liver disease. This study aimed to investigate the role of fibroblast growth factor (FGF)21, a metabolic regulator, in the regulation of chronic-binge alcohol-induced adipose tissue lipolysis. FGF21 KO mice were subjected to chronic-binge alcohol exposure, and epididymal white adipose tissue lipolysis and liver steatosis were investigated. Alcohol exposure caused adipose intracellular cAMP elevation and activation of lipolytic enzymes, leading to FFA mobilization in both WT and FGF21 KO mice. However, alcohol-induced systemic elevation of catecholamine, which is known to be a major player in adipose lipolysis by binding to the β-adrenergic receptor, was markedly inhibited in KO mice. Supplementation with recombinant human FGF21 to alcohol-exposed FGF21 KO mice resulted in an increase in fat loss in parallel with an increase of circulating norepinephrine concentration. Furthermore, alcohol consumption-induced fatty liver was blunted in the KO mice, indicating an inhibition of fatty acid reverse transport from adipose to the liver in the KO mice. Taken together, our studies demonstrate that FGF21 KO mice are protected from alcohol-induced adipose tissue excess-lipolysis through a mechanism involving systemic catecholamine release.     

达格列净对2型糖尿病合并非酒精性脂肪性肝病患者血清FGF-21水平的影响

摘要 目的：分析血清成纤维细胞生长因子-21（FGF-21）与2型糖尿病（T2DM）合并非酒精性脂肪性肝病（NAFLD）患者常见指标及NAFLD纤维化评分（NFS）的相关性,进一步探讨达格列净对T2DM合并NAFLD患者血清FGF-21水平的影响。方法：选取2022年1月至2022年6月徐州医科大学附属徐州市立医院收治的80例T2DM合并NAFLD患者为研究对象（T2DM合并NAFLD组）,选择同期80例T2DM不合并NAFLD患者为T2DM组。收集腰围（WC）、身高、体重数据,计算体重指数（BMI）。测定空腹血糖（FPG）、糖化血红蛋白（HbA1c）、空腹胰岛素（FINS）、甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-c）,低密度脂蛋白胆固醇（LDL-c）、肌酐（Cr）、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST ）、白蛋白（Alb）、血小板计数（PLT）等指标,计算胰岛素抵抗指数（HOMA-IR）、NFS。采用酶联免疫吸附（ELISA）法测定FGF-21水平。比较T2DM组和T2DM合并NAFLD组各项指标的差异,探讨血清FGF-21水平与T2DM合并NAFLD患者其他指标的相关性,Logistic回归分析T2DM合并NAFLD的影响因素,受试者工作特征曲线（ROC）分析各影响因素对T2DM合并NAFLD的诊断价值。将80例T2DM合并NAFLD患者按随机数字表法随机分为二甲双胍组和达格列净组各40例,治疗前后观测各项指标变化,并密切监测不良反应。结果：T2DM合并NAFLD组患者WC、BMI、FINS、HbA1c、TG、AST、ALT、HOMA-IR、NFS及FGF-21均高于 T2DM组（P＜0.05）。相关性分析显示,FGF-21水平与T2DM合并NAFLD组患者WC、BMI、HbA1c、TG、HOMA-IR、NFS均存在正相关（P<0.05）。Logistic回归分析显示,BMI、HbA1c、FGF-21、HOMA-IR为影响T2DM患者合并NAFLD的危险因素。ROC曲线分析显示,BMI、HbA1c、FGF-21、HOMA-IR对T2DM合并NAFLD均具有一定预测价值,其中以FGF-21的预测效能最佳。治疗后,达格列净组TG、AST、ALT、NFS、FGF-21水平较二甲双胍组降低更为明显（P＜0.05）。结论：血清FGF-21水平为T2DM合并NAFLD的危险因素,参与了T2DM合并NAFLD发病及进展,且对T2DM合并NAFLD有较好的预测效能。相较于二甲双胍,达格列净可明显降低T2DM合并NAFLD患者血清FGF-21水平并改善NFS,具有一定程度的肝脏保护作用。     

降脂益生菌对非酒精性脂肪性肝病小鼠胆汁酸代谢及转运的影响和机制初探

目的探讨降脂益生菌(鼠李糖乳杆菌DM9054和植物乳杆菌86066联合制剂)对非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)小鼠胆汁酸代谢及转运的影响和可能机制。方法 18只雄性FXR-/-小鼠随机分为3组(n=6):正常饮食组、高脂饮食组和高脂饮食+降脂益生菌组。其中正常饮食组给予普通饮食和生理盐水灌胃,高脂饮食组给予高脂饮食和生理盐水灌胃,高脂饮食+降脂益生菌组给予高脂饮食和降脂益生菌灌胃。所有小鼠干预12周,处死小鼠1周前行胰岛素耐量试验和腹腔注射葡萄糖耐量试验。小鼠处死后自动生化分析仪检测血脂、胆汁酸及肝功能指标;RT-PCR检测肝脏和回肠组织炎症因子相对表达量;HE染色评估肝脏和回肠组织病理情况;Western blot检测法尼醇受体(Farnesoid X receptor, FXR)通路中的成纤维细胞生长因子15(fibroblast growth factor 15,FGF15)、成纤维细胞生长因子受体4(fibroblast growth factor receptor 4,FGFR4)和小分子异源二聚体(short heterodimer partner, SHP)、胆汁酸合成限速酶胆固醇7α-羟化酶(cholesterol 7α-hydroxylase, CYP7A1)及胆汁酸转运相关的胆盐输出泵(bile salt export pump, BSEP)的蛋白表达。结果和高脂饮食组相比,高脂饮食+降脂益生菌组小鼠血清中胆汁酸含量明显下降(P=0.000 1),FGF15、FGFR4和BSEP蛋白表达水平升高(P=0.009 7、0.024 2、0.000 1),CYP7A1的蛋白表达水平降低(P=0.006 9)。此外,通过降脂益生菌干预还明显改善了高脂饮食FXR-/-小鼠的糖脂代谢紊乱(P=0.002 4)、肝脏脂肪变性、肝脏和回肠组织炎症(P=0.013 8、0.000 1、0.000 1)以及肠黏膜屏障功能(P=0.014 2)。结论降脂益生菌具有类似选择性肠道FXR激动剂的作用,能够通过调控肠道FXR-FGF15通路改善胆汁酸的代谢及转运,进而缓解高脂饮食FXR-/-小鼠的NAFLD。     

Soluble FGFR4 extracellular domain inhibits FGF19-induced activation of FGFR4 signaling and prevents nonalcoholic fatty liver disease

Fibroblast growth factor receptor 4 (FGFR4) is a transmembrane tyrosine kinase receptor that plays a crucial role in the regulation of hepatic bile acid and lipid metabolism. FGFR4 underlies high-fat diet-induced hepatic steatosis, suggesting that inhibition of FGFR4 activation may be an effective way to prevent or treat nonalcoholic fatty liver disease (NAFLD). To determine whether neutralization of FGFR4 ligands by soluble FGFR4 extracellular domain (FGFR4-ECD) can inhibit the activation of FGFR4, we constructed FGFR4-ECD expression vector and showed that FGFR4-ECD was effectively expressed in cells and secreted into culture medium. FGFR4-ECD inhibited FGF19-induced activation of FGFR4 signaling and reduced steatosis of HepG2 induced by palmitic acid in vitro. Furthermore, in a tetracycline-induced fatty liver model, expression of FGFR4-ECD in mouse liver reduced the accumulation of hepatic lipids and partially restored the expression of peroxisome proliferator-activated receptor α (PPARα), which promotes the mitochondrial fatty acid beta-oxidation but is repressed by tetracycline. Taken together, these results demonstrate that FGFR4-ECD can block FGFR4 signaling and prevent hepatic steatosis, highlighting the potential value of inhibition of FGFR4 signaling as a method for therapeutic intervention against NAFLD.     

血清GDF-15、FGF21与非酒精性脂肪性肝病患者肝纤维化和代谢综合征的关系研究

摘要 目的：研究血清生长分化因子15（GDF-15）、成纤维细胞生长因子21（FGF21）与非酒精性脂肪性肝病（NAFLD）患者肝纤维化和代谢综合征（MS）的关系。方法：选取我院2019年1月～2021年2月收治的102例NAFLD患者记作研究组。另选取同期健康体检志愿者100例作为对照组。比较两组血清GDF-15、FGF21与肝纤维化指标水平,并采用Pearson相关性分析明确血清GDF-15、FGF21与肝纤维化指标水平的关系。此外,将研究组患者按照是否并发MS分为MS组以及非MS组,比较MS组以及非MS组血清GDF-15、FGF21水平以及基线资料。采用多因素Logistic回归分析NAFLD并发MS的影响因素。结果：研究组血清GDF-15、FGF21水平高于对照组（均P＜0.05）。研究组血清透明质酸（HA）、层粘连蛋白（LN）、Ⅲ型前胶原（PCⅢ）以及Ⅳ型胶原（ⅣC）水平高于对照组（均P＜0.05）。经Pearson相关性分析发现,血清GDF-15、FGF21水平与血清HA、LN、PCⅢ、ⅣC水平均呈正相关关系（均P＜0.05）。经单因素分析发现,血清天冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）、GDF-15、FGF21水平以及体质量指数、空腹血糖（FPG）、餐后2小时血糖（2hPG）、收缩压（SBP）、舒张压（DBP）、甘油三酯（TG）均和MS有关（均P＜0.05）。经多因素Logistic回归分析发现,血清AST、ALT升高是NAFLD并发MS的保护因素,而体质量指数、GDF-15、FGF21、FPG、2hPG、SBP、DBP、TG升高均是NAFLD并发MS的危险因素（均P＜0.05）。结论：血清GDF-15、FGF21与NAFLD患者肝纤维化以及MS均密切相关,可作为预测NAFLD患者肝纤维化以及MS的辅助性生物学指标。     

肠道菌群影响非酒精性脂肪性肝病的机制及应对策略

非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)的发病率逐年升高,已成为最常见的肝脏疾病之一。目前其发病机制未被完全阐明,尚无有效治疗药物。肠道菌群与人体共生,作为人体的“第二基因组”,其在消化、吸收及代谢中发挥重要作用。新近研究表明,肠道菌群已成为影响NAFLD发生、进展的重要因素,肠道菌群失调和肠肝轴紊乱与非酒精性单纯性脂肪肝(nonalcoholic fatty liver,NAFL)发展为非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)、肝纤维化和肝细胞癌(hepatocellular carcinoma,HCC)密切相关。因此,肠道微生态干预有望成为预防或治疗NAFLD的新手段。本综述主要探讨肠道菌群异常对NAFLD/NASH发病过程、机制的影响及干预措施。     

FGF21 treatment ameliorates alcoholic fatty liver through activation of AMPK-SIRT1 pathway

Fibroblast growth factor 21 （FGF21）, a recently identified member of the FGF superfamily, is mainly secreted from the liver and adipose tissues and plays an important role in improving metabolic syndrome and homeostasis. The aim of this study is to evaluate the role of FGF21 in alcoholic fatty liver disease （AFLD） and to determine if it has a therapeutic effect on AFLD. In this paper, we tested the effect of FGF21 on alcohol-induced liver injury in a murine model of chronic ethanol gavage and alcohol-treated HepG2 cells. Male KM mice received single dose of 5 g/kg ethanol gavage every day for 6 weeks, which induced sig- nificant fatty liver and liver injury. The alcohol-induced fatty liver cell model was achieved by adding ethanol into the medium of HepG2 cell cultures at a final concentration of 75 mM for 9 days. Results showed that treatment with recombinant FGF21 ameliorated alcoholic fatty liver and liver injury both in a murine model of chronic ethanol gavage and alcohol-treated HepG2 cells. In addition, FGF21 treatment down-regulated the hepatic expression of fatty acid synthetic key enzyme, activated hepatic AMPK- SIRT1 pathway and significantly down-regulated hepatic oxidative stress protein. Taken together, FGF21 corrects multiple metabolic parameters of AFLD in vitro and in vivo by activation of the AMPK-SIRT1 pathway.     

老年2型糖尿病患者的血清FGF21水平与临床参数的相关性研究

目的目的对老年糖尿病患者的空腹血浆成纤维细胞生长因子（Fibroblast growth factor21,FGF21）的水平与其临床参数进行相关性分析。方法对辽宁省沈阳市部分社区进行糖尿病普查,对78名65岁以上老年糖尿病患者的空腹血浆FGF21的水平与其临床参数进行相关性分析。其中包括腰围、体重指数（BMI）、血生化学指标、应用针对糖尿病,高血压和血脂异常治疗药物的情况等。结果在单变量分析中,2型糖尿病患者的FGF21水平与是否使用贝特类药物、甘油三酯水平、肌酐水平、腰围和BMI有独立相关性。经过校正年龄,性别和BMI之后进行多元线性回归分析发现,血清FGF21水平与贝特类药物的使用、TG水平、肌酐水平、LDL-C水平、胰高血糖素水平等独立相关。结论在老年2型糖尿病患者中,空腹血清FGF21水平与使用贝特类降脂药物,血脂水平,肾功等密切相关,说明FGF21水平在此类患者的糖脂代谢中占有重要地位。     

FGF19-induced Hepatocyte Proliferation Is Mediated through FGFR4 Activation

FGF19 and FGF21, unique members of the fibroblast growth factor (FGF) family, are hormones that regulate glucose, lipid, and energy homeostasis. Increased hepatocyte proliferation and liver tumor formation have also been observed in FGF19 transgenic mice. Here, we report that, in contrast to FGF19, FGF21 does not induce hepatocyte proliferation in vivo. To identify the mechanism for FGF19-induced hepatocyte proliferation, we explored similarities and differences in receptor specificity between FGF19 and FGF21. We find that although both are able to activate FGF receptors (FGFRs) 1c, 2c, and 3c, only FGF19 activates FGFR4, the predominant receptor in the liver. Using a C-terminal truncation mutant of FGF19 and a series of FGF19/FGF21 chimeric molecules, we determined that amino acids residues 38–42 of FGF19 are sufficient to confer both FGFR4 activation and increased hepatocyte proliferation in vivo to FGF21. These data suggest that activation of FGFR4 is the mechanism whereby FGF19 can increase hepatocyte proliferation and induce hepatocellular carcinoma formation.     

Hepatic FGF21: Its Emerging Role in Inter-Organ Crosstalk and Cancers

Fibroblast growth factor (FGF) 21 is one of the FGF members with special endocrine properties. In the last twenty years, it has attracted intense research and development for its physiological functions that respond to dietary manipulation, pharmacological benefits of improving the macronutrient metabolism, and clinical values as a biomarker of various human diseases. Generally, FGF21 can be produced by major metabolic organs, but only the subgroup from the liver shows canonical endocrine properties, which emphasizes the special value of delineating the unique secretory and functional characteristics of hepatic FGF21. There has been a growth in literature to address the extra-hepatic activities of FGF21, and many striking findings have therefore been published. Yet, they are fragmented and scattered, and controversies are raised from divergent findings. For this reason, there is a need for a systematic and critical evaluation of current research in this aspect. In this review, we focus on the current knowledge about the molecular biology of endocrine FGF21, especially present details on the regulation of circulating levels of FGF21. We also emphasize its emerging roles in inter-organ crosstalk and cancer development.     

Glucose induces FGF21 mRNA expression through ChREBP activation in rat hepatocytes

Fibroblast growth factor 21 (FGF21) has beneficial effects of improving the plasma glucose and lipid profiles in diabetic rodents. Here, we investigated carbohydrate response element binding protein (ChREBP) involvement in the regulation of FGF21 mRNA expression in liver. Glucose stimulation and adenoviral overexpression of dominant active ChREBP increased FGF21 mRNA. Consistently, adenoviral expression of dominant negative Mlx inhibited glucose induction of FGF21 mRNA. Furthermore, deletion studies of mouse FGF21 gene promoter (−2000 to +65 bp) revealed a glucose responsive region between −74 and −52 bp. These findings suggest that FGF21 expression is regulated by ChREBP.     

PPARalpha is a key regulator of hepatic FGF21

The metabolic regulator fibroblast growth factor 21 (FGF21) has antidiabetic properties in animal models of diabetes and obesity. Using quantitative RT-PCR, we here show that the hepatic gene expression of FGF21 is regulated by the peroxisome proliferator-activated receptor alpha (PPARalpha). Fasting or treatment of mice with the PPARalpha agonist Wy-14,643 induced FGF21 mRNA by 10-fold and 8-fold, respectively. In contrast, FGF21 mRNA was low in PPARalpha deficient mice, and fasting or treatment with Wy-14,643 did not induce FGF21. Obese ob/ob mice, known to have increased PPARalpha levels, displayed 12-fold increased hepatic FGF21 mRNA levels. The potential importance of PPARalpha for FGF21 expression also in human liver was shown by Wy-14,643 induction of FGF21 mRNA in human primary hepatocytes, and PPARalpha response elements were identified in both the human and mouse FGF21 promoters. Further studies on the mechanisms of regulation of FGF21 by PPARalpha in humans will be of great interest.     

2 型糖尿病伴脂肪肝患者血浆FGF21水平与肥胖、脂代谢及胰岛素抵抗的相关性

目的:研究2型糖尿病伴脂肪肝患者血浆成纤维细胞生长因子21(FGF21)水平与肥胖、脂代谢及胰岛素抵抗的相关性,为临床诊疗提供依据。方法:选取2013年5月到2015年11月我院收治的2型糖尿病伴脂肪肝患者100例为研究组,另选取同期单纯脂肪肝患者100例为脂肪肝组,健康体检者100例为对照组,比较各组入选次日清晨FGF21、谷丙转氨酶(ALT)、谷草转氨酶(AST)、胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、游离脂肪酸(FFA)、体重指数(BMI)、腰臀比(WHR)、空腹胰岛素(FINS)、空腹血糖(FBG)以及胰岛素抵抗指数(HOMA-IR)。结果:研究组TG、TC、AST、ALT、LDL-C、FFA、FBG、BMI、WHR、FINS、HOMA-IR以及FGF21均显著高于对照组,HDL-C显著低于对照组,比较差异具有统计学意义(P0.05);研究组FFA、TG、FINS、FBG、HOMA-IR以及FGF21显著高于脂肪肝组,BMI和WHR显著低于脂肪肝组,比较差异具有统计学意义(P0.05);相关性分析显示:FGF21与TG、FFA、BMI以及HOMA-IR呈正相关关系(P0.05)。结论:2型糖尿病合并脂肪肝患者FGF21水平会显著升高,且与脂肪代谢、肥胖以及胰岛素抵抗有关。     

FGF15/19 protein levels in the portal blood do not reflect changes in the ileal FGF15/19 or hepatic CYP7A1 mRNA levels

It has been proposed that bile acid suppression of CYP7A1 gene expression is mediated through a gut-liver signaling pathway fibroblast growth factor (FGF)15/19-fibroblast growth factor receptor 4 which is initiated by activation of farnesoid X receptor in the ileum but not in the liver. This study evaluated whether FGF15/19 protein levels in the portal blood reflected changes in FGF15/19 mRNA in the ileum. Studies were conducted in Sprague Dawley rats and New Zealand white rabbits fed regular chow (controls), supplemented with cholesterol (Ch) or cholic acid (CA). After feeding CA, ileal FGF15 mRNA increased 8.5-fold in rats and FGF19 rose 16-fold in rabbits associated with 62 and 75% reduction of CYP7A1 mRNA, respectively. Neither FGF15 nor FGF19 protein levels changed in the portal blood to correspond with the marked increase of FGF15/19 mRNA levels in the ileum or inhibited CYP7A1 expression in the liver. Further, in Ch-fed rats, CYP7A1 mRNA increased 1.9-fold (P < 0.001) although FGF15 mRNA levels in the ileum and portal blood FGF15 protein levels were not decreased. In Ch-fed rabbits, although FGF19 mRNA levels in the ileum and liver did not increase significantly, CYP7A1 mRNA declined 49% (P < 0.05). We were unable to find corresponding changes of FGF15/19 protein levels in the portal blood in rats and rabbits where the mRNA levels of FGF15/19 in the ileum and CYP7A1 in the liver change significantly.     

非酒精性脂肪肝病患者肠道AKK菌与肝功能指标的变化及其影响

目的探究非酒精性脂肪肝病(NAFLD)患者肠道AKK菌及肝功能指标的变化及其影响。方法选取我院2017年3月至2018年11月门诊诊断为NAFLD的109名患者作为NAFLD组。选取同期352名健康志愿者作为对照组。比较两组研究对象体质量指数(BMI)、总胆固醇(TG)、甘油三酯(TC)、高密度脂蛋白(HDLC)、谷丙转氨酶(ALT)、谷草转氨酶(AST)、谷氨酰转肽酶(GGT)的水平及粪便中AKK菌的相对数量。结果NAFLD组患者肠道AKK菌均数为(6.12±1.04),对照组为(6.78±1.07),差异有统计学意义(t=5.664,P<0.001)。NAFLD组患者BMI、LDLC、ALT、AST、GGT的水平显著高于对照组,而HDLC水平显著低于对照组,差异均有统计学意义(均P<0.05)。多因素Logistic回归分析显示AKK菌数量和HDLC为NAFLD的独立保护因素,BMI、ALT、AST、GGT为独立危险因素。结论NAFLD患者肠道中AKK菌数量发生显著变化,AKK菌对NAFLD患者具有保护作用,可为肠道微生物参与NAFLD的发病机制研究提供新的视角。     

Inhibition of lipolysis may contribute to the acute regulation of plasma FFA and glucose by FGF21 in ob/ob mice

FGF21 is a unique member of the fibroblast growth factors (FGFs) and a novel hormone that regulates glucose, lipid, and energy homeostasis. The beneficial effects of FGF21 reported thus far have mostly been from chronic treatments. In order to better understand the mechanism for FGF21 action, we evaluated the acute effects of FGF21 in vivo and in vitro. Here we report that a single injection of FGF21 acutely reduced plasma free fatty acid levels similar to its acute effects on plasma glucose in ob/ob mice. In vitro, FGF21 inhibited lipolysis in adipocytes during a short treatment and reduced total lipase activity. These results demonstrate the potential importance of adipocyte lipolysis to the observed acute improvements in plasma parameters.     

miR‐149 controls non‐alcoholic fatty liver by targeting FGF‐21

Non‐alcoholic fatty liver disease (NAFLD), a lipid metabolism disorder characterized by the accumulation of intrahepatic fat, has emerged as a global public health problem. However, its underlying molecular mechanism remains unclear. We previously have found that miR‐149 was elevated in NAFLD induced by high‐fat diet mice model, whereas decreased by a 16‐week running programme. Here, we reported that miR‐149 was increased in HepG2 cells treated with long‐chain fatty acid (FFA). In addition, miR‐149 was able to promote lipogenesis in HepG2 cells in the absence of FFA treatment. Moreover, inhibition of miR‐149 was capable of inhibiting lipogenesis in HepG2 cells in the presence of FFA treatment. Meanwhile, fibroblast growth factor‐21 (FGF‐21) was identified as a target gene of miR‐149, which was demonstrated by the fact that miR‐149 could negatively regulate the protein expression level of FGF‐21, and FGF‐21 was also responsible for the effect of miR‐149 inhibitor in decreasing lipogenesis in HepG2 cells in the presence of FFA treatment. These data implicate that miR‐149 might be a novel therapeutic target for NAFLD.