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Review
. 2022 Aug 25:13:970292.
doi: 10.3389/fphys.2022.970292. eCollection 2022.

The AMPK pathway in fatty liver disease

Chunqiu Fang  1 , Jianheng Pan  1 , Ning Qu  2 , Yuting Lei  1 , Jiajun Han  1 , Jingzhou Zhang  2 , Dong Han  1
Affiliations
Review

The AMPK pathway in fatty liver disease

Chunqiu Fang et al. Front Physiol. .

Abstract

Lipid metabolism disorders are the primary causes for the occurrence and progression of various liver diseases, including non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) caused by a high-fat diet and ethanol. AMPK signaling pathway plays an important role in ameliorating lipid metabolism disorders. Progressive research has clarified that AMPK signal axes are involved in the prevention and reduction of liver injury. Upregulation of AMK can alleviate FLD in mice induced by alcohol or insulin resistance, type 2 diabetes, and obesity, and most natural AMPK agonists can regulate lipid metabolism, inflammation, and oxidative stress in hepatocytes, consequently regulating FLD in mice. In NAFLD and AFLD, increasing the activity of AMPK can inhibit the synthesis of fatty acids and cholesterol by down-regulating the expression of adipogenesis gene (FAS, SREBP-1c, ACC and HMGCR); Simultaneously, by increasing the expression of fatty acid oxidation and lipid decomposition genes (CPT1, PGC1, and HSL, ATGL) involved in fatty acid oxidation and lipid decomposition, the body's natural lipid balance can be maintained. At present, some AMPK activators are thought to be beneficial during therapeutic treatment. Therefore, activation of AMPK signaling pathway is a potential therapeutic target for disorders of the liver. We summarized the most recent research on the role of the AMPK pathway in FLD in this review. Simultaneously, we performed a detailed description of each signaling axis of the AMPK pathway, as well as a discussion of its mechanism of action and therapeutic significance.

Keywords: AMPK signaling pathway; alcoholic fatty liver; lipid accumulation; lipid metabolism; non-alcoholic fatty liver.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Regulation of AMPK on lipid metabolism in FLD. In the case of non-alcoholic fatty liver disease caused by insulin resistance, type 2 diabetes, obesity, high-fat diet and alcoholic fatty liver disease caused by alcohol, the related proteins in AMPK signaling pathway will be inhibited or promoted, resulting in increased lipid accumulation and decreased fatty acid oxidation. This was reversed when AMPK was treated with AMPK agonists. AMPK, AMP-activated protein kinase; AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide; LKB1, Liver kinase B1; the auxiliary subunit STRAD, STE20 related adaptor protein, and MO25, Mouse protein 25; Sirt1, Silent mating type information regulation two homolog1; CPT1, carnitine acyltransferase one; PGC-1α, peroxisome proliferator-activated receptor γ co-activator -1α; ACC, acetyl-CoA carboxylase; SREBP-1c, Sterol regulatory element-binding protein 1c; FAS, fatty acid synthase; TSC2; mTORC1, mammalian target of rapamycin1; ULK1, unc51 like kinase one; HMGR, 3-hydroxy-3-methylglutaryl-CoA reductase; HSL, Hormone-Sensitive triglyceride lipase; Nrf2/HO-1, nuclear factor erythroid 2-related factor 2/heme oxygenase-1.
FIGURE 2
FIGURE 2
Occurrence and development of AFLD. Alcohol metabolites, including acetaldehyde, will further damage mitochondria, reduce AMPK activity and sensitivity to AMP/ATP, and cause serious lipid accumulation. ROS, reactive oxygen species; CYP2E1, the cytochrome P4502E1; ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NAD+, oxidized nicotinamide adenine dinucleotide.
FIGURE 3
FIGURE 3
Occurrence and development of NAFLD.
See this image and copyright information in PMC

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