Activating Adenosine Monophosphate-Activated Protein Kinase Mediates Fibroblast Growth Factor 1 Protection From Nonalcoholic Fatty Liver Disease in Mice | |
Lin, Qian1,2; Huang, Zhifeng3; Cai, Genxiang4; Fan, Xia3; Yan, Xiaoqing3; Liu, Zhengshuai4; Zhao, Zehua4; Li, Jingya5; Li, Jia5; Shi, Hongxue1,2 | |
刊名 | HEPATOLOGY |
2021-06-01 | |
卷号 | 73期号:6页码:2206-2222 |
ISSN号 | 0270-9139 |
DOI | 10.1002/hep.31568 |
通讯作者 | Tan, Yi(yi.tan@louisville.edu) |
英文摘要 | 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(oHBS)) against NAFLD. Approach and Results FGF1(oHBS) 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(oHBS) reduced oxidative stress by stimulating nuclear translocation of nuclear erythroid 2 p45-related factor 2 (Nrf2) and elevation of antioxidant protein expression. FGF1(oHBS) 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(oHBS). In palmitate-treated hepatic cells, small interfering RNA (siRNA) knockdown of Nrf2 abolished only FGF1(oHBS) antioxidative actions but not improvement of lipid metabolism. In contrast, AMPK inhibition by pharmacological agent or siRNA abolished FGF1(oHBS) 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(oHBS) against high-fat/high-sucrose diet-induced hepatic steatosis. Moreover, FGF1(oHBS) improved high-fat/high-cholesterol diet-induced steatohepatitis and fibrosis in apolipoprotein E knockout mice. Conclusions These findings indicate that FGF1(oHBS) is effective for preventing and reversing liver steatosis and steatohepatitis and acts by activation of AMPK through hepatocyte FGFR4. |
资助项目 | American Diabetes Association[2017YFA0506000] ; NIDCR NIH HHS[R01 DE013686] ; NIGMS NIH HHS[P30 GM127607] ; NIH HHS[DE13686] ; NIH HHS[GM127607] ; National Key R&D Program of China[2017YFA0506000] |
WOS关键词 | INSULIN-RESISTANCE ; HEPATIC STEATOSIS ; AMPK ; STEATOHEPATITIS ; DIET ; PATHOPHYSIOLOGY ; OBESITY ; REDOX ; NRF2 ; FGF1 |
WOS研究方向 | Gastroenterology & Hepatology |
语种 | 英语 |
出版者 | WILEY |
WOS记录号 | WOS:000663150100012 |
内容类型 | 期刊论文 |
源URL | [http://119.78.100.183/handle/2S10ELR8/297149] |
专题 | 中国科学院上海药物研究所 |
通讯作者 | Tan, Yi |
作者单位 | 1.Univ Louisville, Pediat Res Inst, Dept Pediat, Louisville, KY 40202 USA 2.Univ Louisville, Pediat Res Inst, Dept Pharmacol & Toxicol, Louisville, KY 40202 USA 3.Wenzhou Med Univ, Sch Pharmaceut Sci, Chinese Amer Res Inst Diabet Complicat, Wenzhou, Peoples R China 4.Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Nutr & Hlth, Shanghai Inst Biol Sci,CAS Key Lab Nutr Metab & F, Shanghai, Peoples R China 5.Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 6.Univ Louisville, Dept Bioinformat & Biostat, Louisville, KY 40202 USA 7.Wenzhou Med Univ, NAFLD Res Ctr, Dept Hepatol, Affiliated Hosp 1, Wenzhou, Peoples R China 8.Univ Louisville, Dept Med, Louisville, KY 40202 USA 9.Univ Louisville, Diabet & Obes Ctr, Louisville, KY 40202 USA 10.Univ Louisville, Dept Pediat, Div Endocrinol, Louisville, KY 40202 USA |
推荐引用方式 GB/T 7714 | Lin, Qian,Huang, Zhifeng,Cai, Genxiang,et al. Activating Adenosine Monophosphate-Activated Protein Kinase Mediates Fibroblast Growth Factor 1 Protection From Nonalcoholic Fatty Liver Disease in Mice[J]. HEPATOLOGY,2021,73(6):2206-2222. |
APA | Lin, Qian.,Huang, Zhifeng.,Cai, Genxiang.,Fan, Xia.,Yan, Xiaoqing.,...&Tan, Yi.(2021).Activating Adenosine Monophosphate-Activated Protein Kinase Mediates Fibroblast Growth Factor 1 Protection From Nonalcoholic Fatty Liver Disease in Mice.HEPATOLOGY,73(6),2206-2222. |
MLA | Lin, Qian,et al."Activating Adenosine Monophosphate-Activated Protein Kinase Mediates Fibroblast Growth Factor 1 Protection From Nonalcoholic Fatty Liver Disease in Mice".HEPATOLOGY 73.6(2021):2206-2222. |
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