Unregulated mTORC1 activation in the liver: hepatic loss of Depdc5 and Tsc1 synergistically produces liver failure and injury

Abstract

mTORC1 is an important metabolic regulator that responds to insulin/growth factors, nutrients and cellular stresses. DEPDC5 in the GATOR1 complex suppresses mTORC1 in conditions of limited nutrients, while TSC1 in the TSC1/TSC2 complex inhibits mTORC1 during insulin/growth factor deprivation and energetic stresses. Genetic variations in the DEPDC5 gene are associated with increased severity of liver pathologies during chronic hepatitis B and C virus (HBV/HCV) infection, which downregulates TSC1/TSC2. Using mice with liver‐specific Depdc5 deficiency, we examined how Depdc5 affects liver homeostasis, pathophysiology, and its interaction with Tsc1. Depdc5‐deficient mice exhibited enlargement of zone 3 hepatocytes, which progressed into liver damage, inflammation and fibrosis at later age. Double deletion of both Tsc1 and Depdc5 (DKO) produced synergistic mTORC1 activation, which was much more than what was observed from single Tsc1 or Depdc5 knockout mice. DKO mice experienced pronounced and widespread hepatocyte damage, and exhibited externally visible liver failure phenotypes, such as jaundice and systemic growth defects. Through systemic transcriptome analysis, we identified superoxide accumulation and oxidative damage as the main pathogenetic features distinguishing these mice from other mTORC1 models. Indeed, mTORC1 inhibition, as well as superoxide reduction, were sufficient to eliminate most pathological phenotypes we observed in mTORC1‐hyperactivated liver tissues. The current findings provide the genetic evidence supporting that growth factor/insulin‐regulated (Tsc1) and nutrient‐regulated (Depdc5) pathways genetically interact to coordinate mTORC1 activation. In addition, this multi‐pathway method for mTORC1 hyperactivation explains how DEPDC5 perturbations in humans aggravate HBV/HCV pathologies, which inhibit TSC1 and activate mTORC1.Support or Funding InformationR01DK102850, R01DK111465 and R01DK114131 to JHL, F31DK117610 to AH, K01AG061236 to MK, T32AG000114, T32GM008322, P30AG024824, P30AR069620, P30DK034933, P30DK089503 and P30CA046592