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.

NmFGF1-Regulated Glucolipid Metabolism and Angiogenesis Improves Functional Recovery in a Mouse Model of Diabetic Stroke and Acts via the AMPK Signaling Pathway

“…It has also been reported that adiponectin improves the function of endothelial cells by activating the AMPK pathway (Chen et al, 2009). Moreover, the activation of AMPK was shown to mediate the protection of fibroblast growth factor 1 from non-alcoholic fatty liver disease in mice by improving lipid metabolism (Lin et al, 2020). These findings suggested that AMPK may be involved in the protective effect of nmFGF1 on stroke in type 2 diabetic (T2D) mice and acts by regulating glucolipid metabolism and angiogenesis.…”

Ferulic Acid Ameliorates Hepatic Inflammation and Fibrotic Liver Injury by Inhibiting PTP1B Activity and Subsequent Promoting AMPK Phosphorylation

“…AMPK, as a pivotal player in maintaining cellular energy homeostasis, is reported to regulate multiple metabolic processes. Previous articles indicated that the loss of AMPK activation significantly aggravated liver inflammation and lipid disorders in mouse fibrotic models ( Lin et al, 2020 ; Zhao et al, 2020 ). In addition, the protective functions of AMPK phosphorylation are also highlighted recently, including preventing oxidative stress and attenuating alcoholic liver disease progression ( Lu et al, 2021 ).…”

“…Most recently, Qian Lin et al constructed liver-specific AMPK knockout mice and investigated the specific role of phosphorylated AMPK in fibrotic steatohepatitis. The hepatic depletion of AMPK completely disrupted hepatic lipid metabolism, triggered inflammatory response and aggregated liver fibrosis in a western diet-induced liver steatotic mouse model ( Lin et al, 2020 ). Collectively, considering the vital role that AMPK plays in the progression of fibrotic liver injury, the identification of novel drugs targeting AMPK is urgently needed.…”

Caveolin-1 Alleviates Acetaminophen-Induced Fat Accumulation in Non-Alcoholic Fatty Liver Disease by Enhancing Hepatic Antioxidant Ability via Activating AMPK Pathway

“…Recently, AMPK, a diffusely known energy sensor, has been reported to play a crucial role in antioxidant responses ( Wu et al, 2018 ; Lin et al, 2020 ). We measured AMPK activity by detecting phosphorylation of AMPKα subunit at threonine 172.…”