Dataset Information

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

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.

SUBMITTER: Lin Q

PROVIDER: S-EPMC8082952 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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

Lin Qian Q Huang Zhifeng Z Cai Genxiang G Fan Xia X Yan Xiaoqing X Liu Zhengshuai Z Zhao Zehua Z Li Jingya J Li Jia J Shi Hongxue H Kong Maiying M Zheng Ming-Hua MH Conklin Daniel J DJ Epstein Paul N PN Wintergerst Kupper A KA Mohammadi Moosa M Cai Lu L Li Xiaokun X Li Yu Y Tan Yi Y

Hepatology (Baltimore, Md.) 20210601 6

<h4>Background and aims</h4>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<sup>△HBS</sup> ) against NAFLD.<h4>Approach and results</h4>FGF1<sup>△HBS</sup> administration was effective in 9-month-old diabetic mice carrying a homozy ...[more]

PMID: 32965675

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Project description:Background: Pulmonary fibrosis (PF) is a devastating interstitial lung disease and characterized by an abnormal accumulation of extracellular matrix (ECM). Nintedanib (NDN) and pirfenidone are two approved therapies for PF, but their potential side-effects have been reported. Recently, the use of natural supplements for PF is attracting attention. Alpha-mangostin (α-MG) is an active xanthone-type compound isolated from the nutritious fruit mangosteen. Purpose: In the present study, the potential effect and underlying mechanism of α-MG were evaluated in bleomycin (BLM)-induced PF and activated primary lung fibroblasts (PLFs). Methods: Histopathological changes and collagen deposition were analyzed via hematoxylin-eosin staining and Masson staining, the expression of nicotinamide adenine dinucleotide phosphate oxidase-4 (NOX4) involved in oxidative stress in lung tissues was analyzed by immunochemistry staining. The expressions of α-smooth muscle actin (α-SMA), collagen I (Col I), p-adenosine 5'-monophosphate-activated protein kinase (AMPK)/AMPK, and NOX4 were detected by Western blot, immunofluorescence or RT-PCR, and effects of α-MG on cell viability were detected using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide. Results: In vivo results demonstrated that α-MG treatment (10 mg/kg/day) significantly ameliorated BLM-induced deposition of ECM in lung tissues. Moreover, α-MG could inhibit protein expressions of α-SMA and Col I as well as its mRNA levels. In addition, α-MG also significantly inhibited transforming growth factor-β1/Smad2/3 pathway and regulated the protein expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in lung tissues. In vitro results demonstrated that α-MG significantly increased p-AMPK/AMPK but reduced the protein expression level of α-SMA and Col I as well as NOX4 in activated PLFs. Further study demonstrated that these improvement effects were significantly blocked by compound C. Conclusion: α-MG treatment significantly decreased oxidative stress in lungs partly by activating AMPK mediated signaling pathway in BLM-induced PF and activated PLFs and decreased the deposition of ECM. The present study provides pharmacological evidence to support therapeutic application of α-MG in the treatment of PF.

Dataset Information

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

Background and aims

Approach and results

Conclusions

Publications

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

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