Qian Lin1, Zhifeng Huang2, Genxiang Cai3, Xia Fan2, Xiaoqing Yan2, Zhengshuai Liu3, Zehua Zhao3, Jingya Li4, Jia Li4, Hongxue Shi1, Maiying Kong5, Ming-Hua Zheng6, Daniel J Conklin7, Paul N Epstein1, Kupper A Wintergerst1,8,9, Moosa Mohammadi10, Lu Cai1,9, Xiaokun Li2, Yu Li3, Yi Tan1,9. 1. Departments of Pediatrics, Pharmacology & Toxicology, Pediatric Research Institute, University of Louisville, Louisville, KY, USA. 2. Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China. 3. CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. 4. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. 5. Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY, USA. 6. NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. 7. Department of Medicine and Diabetes and Obesity Center, University of Louisville, Louisville, KY, USA. 8. Division of Endocrinology, Department of Pediatrics, University of Louisville, Louisville, KY, USA. 9. Wendy L. Novak Diabetes Care Center, Louisville, KY, USA. 10. Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY, USA.
Abstract
BACKGROUND AND AIMS: 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△HBS ) against NAFLD. APPROACH AND RESULTS: FGF1△HBS 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△HBS reduced oxidative stress by stimulating nuclear translocation of nuclear erythroid 2 p45-related factor 2 (Nrf2) and elevation of antioxidant protein expression. FGF1△HBS 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△HBS . In palmitate-treated hepatic cells, small interfering RNA (siRNA) knockdown of Nrf2 abolished only FGF1△HBS antioxidative actions but not improvement of lipid metabolism. In contrast, AMPK inhibition by pharmacological agent or siRNA abolished FGF1△HBS 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△HBS against high-fat/high-sucrose diet-induced hepatic steatosis. Moreover, FGF1△HBS improved high-fat/high-cholesterol diet-induced steatohepatitis and fibrosis in apolipoprotein E knockout mice. CONCLUSIONS: These findings indicate that FGF1△HBS is effective for preventing and reversing liver steatosis and steatohepatitis and acts by activation of AMPK through hepatocyte FGFR4.
BACKGROUND AND AIMS: 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△HBS ) against NAFLD. APPROACH AND RESULTS: FGF1△HBS 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△HBS reduced oxidative stress by stimulating nuclear translocation of nuclear erythroid 2 p45-related factor 2 (Nrf2) and elevation of antioxidant protein expression. FGF1△HBS 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△HBS . In palmitate-treated hepatic cells, small interfering RNA (siRNA) knockdown of Nrf2 abolished only FGF1△HBS antioxidative actions but not improvement of lipid metabolism. In contrast, AMPK inhibition by pharmacological agent or siRNA abolished FGF1△HBS 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△HBS against high-fat/high-sucrose diet-induced hepatic steatosis. Moreover, FGF1△HBS improved high-fat/high-cholesterol diet-induced steatohepatitis and fibrosis in apolipoprotein E knockout mice. CONCLUSIONS: These findings indicate that FGF1△HBS is effective for preventing and reversing liver steatosis and steatohepatitis and acts by activation of AMPK through hepatocyte FGFR4.
Authors: Stephen L Slocum; John J Skoko; Nobunao Wakabayashi; Susan Aja; Masayuki Yamamoto; Thomas W Kensler; Dionysios V Chartoumpekis Journal: Arch Biochem Biophys Date: 2015-12-14 Impact factor: 4.013
Authors: Hongfei Ge; Jun Zhang; Yan Gong; Jamila Gupte; Jay Ye; Jennifer Weiszmann; Kim Samayoa; Suzanne Coberly; Jonitha Gardner; Huilan Wang; Tim Corbin; Danny Chui; Helene Baribault; Yang Li Journal: J Biol Chem Date: 2014-09-09 Impact factor: 5.157
Authors: Jae Myoung Suh; Johan W Jonker; Maryam Ahmadian; Regina Goetz; Denise Lackey; Olivia Osborn; Zhifeng Huang; Weilin Liu; Eiji Yoshihara; Theo H van Dijk; Rick Havinga; Weiwei Fan; Yun-Qiang Yin; Ruth T Yu; Christopher Liddle; Annette R Atkins; Jerrold M Olefsky; Moosa Mohammadi; Michael Downes; Ronald M Evans Journal: Nature Date: 2014-07-16 Impact factor: 49.962