Liver-adipose tissue crosstalk in alcohol-associated liver disease: The role of mTOR

BACKGROUND: Alcohol-associated liver disease (ALD) is a major chronic liver disease around the world without successful treatment. Acute alcoholic hepatitis is one of the most severe forms of ALD with high mortality, which is often associated with binge drinking. Alcohol drinking dysregulates lipid metabolism, increases adipose tissue lipolysis, and induces liver steatosis and adipose tissue atrophy. Increasing evidence implicates that crosstalk of liver and adipose tissue in the pathogenesis of ALD. Mechanistic target of rapamycin (mTOR) is a phosphatidylinositol 3-kinase (PI3K)-like serine/threonine protein kinase that regulates lipid metabolism, cell proliferation and autophagy. However, the role of mTOR in regulating adipose-liver crosstalk in binge drinking-induced organ damage remains unclear. METHODS: We generated liver-specific and adipocyte-specific regulatory-associated protein of mTOR (Rptor) knockout (Rptor(LKO) and Rptor(AKO)) as well as Mtor knockout (Mtor(LKO) and Mtor(AKO)) mice, by crossing Rptor(flox) and Mtor(flox) mice with albumin Cre or adiponectin Cre mice, respectively. In addition, we generated liver and adipocyte double deletion of Rptor or Mtor (Mtor(LAKO) and Rptor(LAKO)) mice. The knockout mice with their matched wild-type littermates (Rptor(WT) and Mtor(WT)) were subjected to acute gavage of 7 g/kg ethanol. RESULTS: Mice with adipocyte deletion of Rptor or Mtor developed hepatomegaly and adipose tissue atrophy. Alcohol gavage increased liver injury, hepatic steatosis and inflammation in mouse livers as demonstrated by elevated serum alanine aminotransferase activities, increased hepatic levels of triglyceride and increased hepatic numbers of CD68 positive macrophages in mouse livers after alcohol gavage. Liver injury was further exacerbated by deletion of adipocyte Rptor or Mtor. Serum adipokine array analysis revealed that increased levels of pro-inflammatory cytokines IL-6 and TNFα as well as chemokine MCP-1 following acute alcohol gavage in wild-type mice, which were further increased in adipocyte-specific Mtor or Rptor knockout mice. Conversely, levels of anti-inflammatory cytokine IL-10 decreased in adipocyte-specific Mtor or Rptor knockout mice. The levels of circulating fibroblast growth factor 21 (FGF21) increased whereas levels of circulating adiponectin and fetuin A decreased in wild-type mice after alcohol gavage. Intriguingly, adipocyte-specific Mtor or Rptor knockout mice already had decreased basal level of FGF21 which increased by alcohol gavage. Moreover, adipocyte-specific Mtor or Rptor knockout mice already had increased basal level of adiponectin and decreased fetuin A which were not further changed by alcohol gavage. CONCLUSIONS: Adipocyte but not hepatocyte ablation of Mtor pathway contributes to acute alcohol-induced liver injury with increased inflammation. Our results demonstrate the critical role of adipocyte mTOR in regulating the adipose-liver crosstalk in ALD.