Metformin-induced TTP mediates communication between Kupffer cells and hepatocytes to alleviate hepatic steatosis by regulating lipophagy and necroptosis.

ABSTRACT

OBJECTIVE: Emerging evidence suggests that crosstalk between Kupffer cells (KCs) and hepatocytes protects against non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms that lead to the reduction of steatosis in NAFLD remain obscure. METHODS: Ttp+/+ and Ttp-/- mice were fed with a high-fat diet. Hepatic steatosis was analyzed by Nile Red staining and measurement of inflammatory cytokines. Lipid accumulation and cell death were evaluated in co-culture systems with primary hepatocytes and KCs derived from either Ttp+/+ or Ttp-/- mice. RESULTS: Tristetraprolin (TTP), an mRNA binding protein, was essential for the protective effects of metformin in NAFLD. Metformin activated TTP via the AMPK-Sirt1 pathway in hepatocytes and KCs. TTP inhibited TNF-α production in KCs, which in turn decreased hepatocyte necroptosis. Downregulation of Rheb expression by TTP promoted hepatocyte lipophagy via mTORC1 inhibition and increased nuclear translocation of transcription factor-EB (TFEB). Consistently, TTP-deficient NAFLD mice failed to respond to metformin with respect to alleviation of hepatic steatosis, protection of hepatocyte necroptosis, or induction of lipophagy. CONCLUSIONS: TTP, which is essential for the protective effects of metformin, may represent a novel primary therapeutic target in NAFLD.