Autophagy Dysregulation in Metabolic Associated Fatty Liver Disease: A New Therapeutic Target

Abstract

Metabolic associated fatty liver disease (MAFLD) is one of the most common causes of chronic liver disease worldwide. To date, there is no FDA-approved treatment, so there is an urgent need to determine its pathophysiology and underlying molecular mechanisms. Autophagy is a lysosomal degradation pathway that removes damaged organelles and misfolded proteins after cell injury through endoplasmic reticulum stress or starvation, which inhibits apoptosis and promotes cell survival. Recent studies have shown that autophagy plays an important role in removing lipid droplets from hepatocytes. Autophagy has also been reported to inhibit the production of pro-inflammatory cytokines and provide energy for the hepatic stellate cells activation during liver fibrosis. Thyroid hormone, irisin, melatonin, hydrogen sulfide, sulforaphane, DA-1241, vacuole membrane protein 1, nuclear factor erythroid 2-related factor 2, sodium-glucose co-transporter type-2 inhibitors, immunity-related GTPase M, and autophagy-related gene 7 have been reported to ameliorate MAFLD via autophagic induction. Lipid receptor CD36, SARS-CoV-2 Spike protein and leucine aminopeptidase 3 play a negative role in the autophagic function. This review summarizes recent advances in the role of autophagy in MAFLD. Autophagy modulates major pathological changes, including hepatic lipid metabolism, inflammation, and fibrosis, suggesting the potential of modulating autophagy for the treatment of MAFLD.

Keywords: MAFLD; NAFLD; autophagy; fatty liver disease; metabolic disease.

Figure 1

Regulation of autophagy on fatty liver pathogenic pathways. Autophagy inhibits hepatic steatosis, inflammation, oxidative stress, ER stress, apoptosis, and M1 KCs polarization. Autophagy induces M2 KCs. Autophagy may play a dual role in HSC activation. aHSCs: activated hepatic stellate cells; BAT: brown adipose tissue; ER: endoplasmic reticulum; FFAs: free fatty acid; KCs: Kupffer cells; qHSCs: quiescent hepatic stellate cells; WAT: white adipose tissue.

Figure 2

Functional enrichment analysis of protein–protein interaction networks. (A) Autophagy-related markers, proteins, and newly discovered autophagy regulators were selected to predict their interaction network via STRING. (B) The indicating colors and content of the nodes and the confidence of edges. ATN1: Atrophin-1; CASP3: caspase-3; DIO3: thyroid hormones; FNDC5: Irisin; HMOX1: HO-1; MTNR1B: melatonin receptor type 1B; NFE2L2: Nfr2; PIK3CA: PI3K; PRKAB1: AMPK; SQSTM1: p62; MAP1LC3B: LC3B; TMPRSS2: SARS-CoV-2 S protein.