The essential effect of mTORC1-dependent lipophagy in non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a chronic progressive liver disease with increasing prevalence. Lipophagy is a type of programmed cell death that plays an essential role in maintaining the body’s balance of fatty acid metabolism. However, the livers of NAFLD patients are abnormally dysregulated in lipophagy. mTORC1 is a critical negative regulator of lipophagy, which has been confirmed to participate in the process of lipophagy through various complex mechanisms. Therefore, targeting mTORC1 to restore failed autophagy may be an effective therapeutic strategy for NAFLD. This article reviews the main pathways through which mTORC1 participates in the formation of lipophagy and the intervention effect of mTORC1-regulated lipophagy in NAFLD, providing new therapeutic strategies for the prevention and treatment of NAFLD in the future.

Regulation of Benzo[a]pyrene-Induced Hepatic Lipid Accumulation through CYP1B1-Induced mTOR-Mediated Lipophagy

“…These results demonstrate that mTOR is specifically regulated by CYP1B1. mTOR is also well known to inhibit lipophagy by affecting genes involved in the induction of autophagosomes [34,35,49]. In nutrient-rich conditions, activated mTOR suppresses the formation of autophagosomes.…”

“…In nutrient-rich conditions, activated mTOR suppresses the formation of autophagosomes. Conversely, when nutrients are insufficient, mTOR is inactivated, which induces autophagosome formation [33,35]. Although the importance of mTOR in lipid metabolism is gradually emerging, research on the exact mechanisms of its involvement is still insufficient.…”

“…It regulates gene transcription and nutrient uptake in response to intracellular nutrients, stressors, and energy levels, influencing cell growth, aging, and metabolism. Interestingly, it has been found that mTOR is also involved in lipid metabolism, where it has been discerned that it suppresses the induction of lipophagy by inhibiting autophagosome formation [35,36]. Moreover, mTOR regulates the expression of lysosomerelated genes by controlling the translocation of the microphthalmia subfamily (MiTF/TFE family: MITF, TFEB, TFE3, and TFEC), which are known as master transcription factors of lipophagy [37,38].…”

Cell-type specific role of autophagy in the liver and its implications in non-alcoholic fatty liver disease

“…The key lipase involved in this process is known as lysosomal lipase[ 29 ]. Defects in hepatocyte lipophagy are suspected to be a major cause of early NAFLD development in humans[ 60 - 62 ]. In addition to lipophagy, CMA also plays a key role in the lipolysis of TAGs within hepatocytes[ 63 ].…”