Departments of Pediatrics, Pharmacology & Toxicology, Pediatric Research Institute, University of Louisville, Louisville, KY, USA.
Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
Hepatology. 2021 Jun;73(6):2206-2222. doi: 10.1002/hep.31568.
Fibroblast growth factor (FGF) 1 demonstrated protection against nonalcoholic fatty liver disease (NAFLD) in type 2 diabetic and obese mice by an uncertain mechanism. This study investigated the therapeutic activity and mechanism of a nonmitogenic FGF1 variant carrying 3 substitutions of heparin-binding sites (FGF1 ) against NAFLD.
FGF1 administration was effective in 9-month-old diabetic mice carrying a homozygous mutation in the leptin receptor gene (db/db) with NAFLD; liver weight, lipid deposition, and inflammation declined and liver injury decreased. FGF1 reduced oxidative stress by stimulating nuclear translocation of nuclear erythroid 2 p45-related factor 2 (Nrf2) and elevation of antioxidant protein expression. FGF1 also inhibited activity and/or expression of lipogenic genes, coincident with phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and its substrates. Mechanistic studies on palmitate exposed hepatic cells demonstrated that NAFLD-like oxidative damage and lipid accumulation could be reversed by FGF1 . In palmitate-treated hepatic cells, small interfering RNA (siRNA) knockdown of Nrf2 abolished only FGF1 antioxidative actions but not improvement of lipid metabolism. In contrast, AMPK inhibition by pharmacological agent or siRNA abolished FGF1 benefits on both oxidative stress and lipid metabolism that were FGF receptor (FGFR) 4 dependent. Further support of these in vitro findings is that liver-specific AMPK knockout abolished therapeutic effects of FGF1 against high-fat/high-sucrose diet-induced hepatic steatosis. Moreover, FGF1 improved high-fat/high-cholesterol diet-induced steatohepatitis and fibrosis in apolipoprotein E knockout mice.
These findings indicate that FGF1 is effective for preventing and reversing liver steatosis and steatohepatitis and acts by activation of AMPK through hepatocyte FGFR4.
成纤维细胞生长因子 (FGF) 1 通过不确定的机制对 2 型糖尿病和肥胖小鼠的非酒精性脂肪性肝病 (NAFLD) 具有保护作用。本研究研究了携带 3 个肝素结合位点取代的非有丝分裂 FGF1 变异体 (FGF1) 对 NAFLD 的治疗活性和机制。
FGF1 给药对携带瘦素受体基因 (db/db) 纯合突变的 9 月龄糖尿病小鼠有效，可降低肝重、脂质沉积和炎症，并减轻肝损伤。FGF1 通过刺激核红细胞 2 p45 相关因子 2 (Nrf2) 的核易位和抗氧化蛋白表达的升高来减少氧化应激。FGF1 还抑制脂肪生成基因的活性和/或表达，同时伴随着腺苷单磷酸激活蛋白激酶 (AMPK) 的磷酸化及其底物。在脂肪酸暴露的肝细胞的机制研究中，发现 FGF1 可逆转类似 NAFLD 的氧化损伤和脂质积累。在脂肪酸处理的肝细胞中，Nrf2 的小干扰 RNA (siRNA) 敲低仅消除了 FGF1 的抗氧化作用，而没有改善脂质代谢。相反，通过药理学试剂或 siRNA 抑制 AMPK 消除了 FGF1 对氧化应激和脂质代谢的作用，而这些作用依赖于成纤维细胞生长因子受体 (FGFR) 4。这些体外发现的进一步支持是，肝特异性 AMPK 敲除消除了 FGF1 对高脂肪/高蔗糖饮食诱导的肝脂肪变性的治疗作用。此外，FGF1 改善了载脂蛋白 E 敲除小鼠的高脂肪/高胆固醇饮食诱导的脂肪性肝炎和纤维化。
这些发现表明，FGF1 可有效预防和逆转肝脂肪变性和脂肪性肝炎，并通过肝细胞 FGFR4 激活 AMPK 发挥作用。
