Activating Adenosine Monophosphate-Activated Protein Kinase Mediates Fibroblast Growth Factor 1 Protection From Nonalcoholic Fatty Liver Disease in Mice

doi:10.1002/hep.31568

	Activating Adenosine Monophosphate-Activated Protein Kinase Mediates Fibroblast Growth Factor 1 Protection From Nonalcoholic Fatty Liver Disease in Mice
	Lin, Qian 1,2; Huang, Zhifeng 3; Cai, Genxiang 4; Fan, Xia 3; Yan, Xiaoqing 3; Liu, Zhengshuai 4; Zhao, Zehua 4; Li, Jingya 5; Li, Jia 5; Shi, Hongxue 1,2
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.