Role of mechanistic target of rapamycin in autophagy and alcohol-associated liver disease

Abstract

Mechanistic target of rapamycin (mTOR) is a serine-threonine kinase and a cellular sensor for nutrient and energy status, which is critical in regulating cell metabolism and growth by governing the anabolic (protein and lipid synthesis) and catabolic process (autophagy). Alcohol-associated liver disease (ALD) is a major chronic liver disease worldwide that carries a huge financial burden. The spectrum of the pathogenesis of ALD includes steatosis, fibrosis, inflammation, ductular reaction, and eventual hepatocellular carcinoma, which is closely associated with metabolic changes that are regulated by mTOR. In this review, we summarized recent progress of alcohol consumption on the changes of mTORC1 and mTORC2 activity, the potential mechanisms and possible impact of the mTORC1 changes on autophagy in ALD. We also discussed the potential beneficial effects and limitations of targeting mTORC1 against ALD.

Keywords: alcohol-associated liver disease; autophagy; ethanol; mTOR; transcription factor EB.

Graphical abstract

Figure 1.

The upstream signaling network regulating mTORC1 and mTORC2. mTORC1 integrates four major signals: growth factors, energy status, oxygen, and amino acids, which regulate cellular processes that are involved in the promotion of cell growth, proliferation, and metabolism. mTORC2 mainly regulates AKT activation and insulin sensitivity. 1) Growth factor-mediated mTORC1 activation. Growth factors, such as insulin/IGFs, bind to their receptors and activate PI3K to convert PtdIns(4, 5)P2 to PtdIns(3–5)P3, which subsequently activate PDK1 to promote AKT phosphorylation. AKT phosphorylates TSC2 on multiple sites to inhibit its GAP activity for the small GTPase RHEB. GTP-loaded RHEB then activates mTORC1. 2) Amino acids. Amino acids stimulate mTORC1 by promoting the conversion of small GTPase Rag heterodimers to the active form, in which Rag A or Rag B is loaded with GTP and Rag C or Rag D is loaded with GDP. The active RAG heterodimer recruits mTORC1 to the surface of the lysosome, where RHEB binds and activates mTORC1. 3) Energy status. In response to low energy (high AMP/ATP ratio) or glucose, activated AMPK phosphorylates TSC2 of TSC1/TSC2 complex, or phosphorylates RAPTOR, which leads to mTORC1 inhibition. AKT, protein kinase B; AMPK, AMP-activated protein kinase; IGFs, insulin-like growth factors; L, leucine; mTORC1, mechanistic target of rapamycin complex 1; PDK1, phosphoinositide-dependent kinase 1; PtdIns(4, 5)P2, phosphatidylinositol-4,5-bisphosphate; PtdIns(3–5)P3, phosphatidylinositol-3,4,5-triphosphate; R, arginine; Rag, RAS-related GTP-binding protein; RAPTOR, regulatory-associated protein of mTOR; RHEB, RAS homologue enriched in brain.

Figure 2.

Acute and chronic alcohol exposure have distinctive effects on mechanistic target of rapamycin complex 1 (mTORC1) and autophagy in mouse livers. A: acute ethanol binge induces autophagy by inhibiting mTORC1 and mechanistic target of rapamycin complex 2 (mTORC2). Ethanol is metabolized in the liver by alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1) to increase reactive oxygen species (ROS) production, which may lead to the inhibition of both mTORC1 and mTORC2 by yet unknown mechanisms. Decreased mTORC1 then promotes hepatic autophagy induction. Decreased mTORC2 leads to decreased protein kinase B (AKT) phosphorylation and activation resulting in decreased Forkhead box O-3 (FOXO3) phosphorylation and increased FOXO3 nuclear translocation. Activated FOXO3 increases the expression of autophagy related genes and autophagy induction to protect against acute alcohol-induced liver injury. B: chronic feeding plus acute ethanol binge impairs autophagy by increasing mTORC1 activation. Chronic feeding plus acute ethanol binge increases lysosomal RagA and decreases DEP-domain-containing mTOR-interacting protein (DEPTOR) resulting in mTOR lysosomal translocation and mTORC1 activation. Increased mTORC1 activation promotes the phosphorylation and cytosolic retention of transcription factor EB (TFEB) resulting in decreased nuclear TFEB translocation. Decreased nuclear TFEB reduces the expression of lysosomal and –autophagy-related genes as well as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) the master regulator of mitochondrial biogenesis. Torin1 inhibits mTORC1 and rescues alcohol-induced defective TFEB resulting in increased biogenesis of lysosomes and mitochondria as well as autophagy to protect against alcohol-induced liver injury. Whether chronic ethanol feeding would affect mTORC2 remains to be determined.