title: Fibroblast growth factor 21 deficiency exacerbates chronic alcohol-induced hepatic steatosis and injury.
abstract: Fibroblast growth factor 21 (FGF21) is a hepatokine that regulates glucose and lipid metabolism in the liver. We sought to determine the role of FGF21 in hepatic steatosis in mice exposed to chronic alcohol treatment and to discern underlying mechanisms. Male FGF21 knockout (FGF21 KO) and control (WT) mice were divided into groups that were fed either the Lieber DeCarli diet containing 5% alcohol or an isocaloric (control) diet for 4 weeks. One group of WT mice exposed to alcohol received recombinant human FGF21 (rhFGF21) in the last 5 days. Liver steatosis and inflammation were assessed. Primary mouse hepatocytes and AML-12 cells were incubated with metformin or rhFGF21. Hepatic genes and the products involved in in situ lipogenesis and fatty acid β-oxidation were analyzed. Alcohol exposure increased circulating levels and hepatic expression of FGF21. FGF21 depletion exacerbated alcohol-induced hepatic steatosis and liver injury, which was associated with increased activation of genes involved in lipogenesis mediated by SREBP1c and decreased expression of genes involved in fatty acid β-oxidation mediated by PGC1α. rhFGF21 administration reduced alcohol-induced hepatic steatosis and inflammation in WT mice. These results reveal that alcohol-induced FGF21 expression is a hepatic adaptive response to lipid dysregulation. Targeting FGF21 signaling could be a novel treatment approach for alcoholic steatohepatitis.
authors: School of Pharmacy and First Affiliate Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.|Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
authors: Yanlong
authors: Y
authors: Liu
authors: School of Pharmacy and First Affiliate Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.|Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA.|Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang, 325035, China.
authors: Cuiqing
authors: C
authors: Zhao
authors: School of Pharmacy and First Affiliate Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.
authors: Jian
authors: J
authors: Xiao
authors: Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
authors: Liming
authors: L
authors: Liu
authors: Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
authors: Min
authors: M
authors: Zhang
authors: School of Life Sciences, Northwest University, Xi'an, Shaanxi, 710069, China.
authors: Cuiling
authors: C
authors: Wang
authors: Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA.|Three George Central Hospital, Chongqing, 404000, China.
authors: Guicheng
authors: G
authors: Wu
authors: School of Pharmacy and First Affiliate Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.
authors: Ming-Hua
authors: MH
authors: Zheng
authors: School of Pharmacy and First Affiliate Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.
authors: Lan-Man
authors: LM
authors: Xu
authors: School of Pharmacy and First Affiliate Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.
authors: Yong-Ping
authors: YP
authors: Chen
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
authors: Moosa
authors: M
authors: Mohammadi
authors: Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
authors: Shao-Yu
authors: SY
authors: Chen
authors: Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
authors: Matthew
authors: M
authors: Cave
authors: Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA.|Robley Rex VA Medical Center, Louisville, KY, 40206, USA.
authors: Craig
authors: C
authors: McClain
authors: School of Pharmacy and First Affiliate Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.|Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang, 325035, China.
authors: Xiaokun
authors: X
authors: Li
authors: School of Pharmacy and First Affiliate Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.|Alcohol Research Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
authors: Wenke
authors: W
authors: Feng
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects / Q000097:blood; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005235:Fatty Liver, Alcoholic / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics* / Q000627:therapeutic use; D015870:Gene Expression; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D050155:Lipogenesis; D008099:Liver / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D011994:Recombinant Proteins / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D015850:Interleukin-6; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C414620:fibroblast growth factor 21; C577686:interleukin-6, mouse; D005346:Fibroblast Growth Factors