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.

Oridonin restores hepatic lipid homeostasis in an LXRα-ATGL/EPT1 axis-dependent manner

“…Steatosis impairs the hepatocyte membrane integrity leading to inflammatory responses or fibrosis [ 7 , 37 ]. Several lines of evidence support that NAFLD and hepatic steatosis result in lipid disorder between TG and PE.…”

Autophagy: A Cellular Guardian against Hepatic Lipotoxicity

“…Interestingly, lipids alter cellular autophagy, playing an important role mediating lipotoxic injury in NAFLD [ 33 ]. In fact, autophagy has been shown to be impaired in animal and human NAFLD and NASH [ 34 ].…”

Traditional Chinese medicines and natural products targeting immune cells in the treatment of metabolic-related fatty liver disease

“…Autophagy is a cellular process that involves the degradation of damaged or dysfunctional cellular components, including pathogens and cellular debris, by lysosomal enzymes (Mizushima and Komatsu, 2011). It has been suggested that impaired autophagy may contribute to the development and progression of MAFLD, as it can lead to the accumulation of lipid droplets, OS, and inflammation in hepatocytes (Chen and Lin, 2022). Immune cells also play a crucial role in the pathogenesis of MAFLD, as they are involved in the processes of inflammation, fibrosis, and hepatic steatosis (Torre et al, 2021).…”