| First Author | Park J | Year | 2023 |
| Journal | Metabolism | Volume | 141 |
| Pages | 155516 | PubMed ID | 36773805 |
| Mgi Jnum | J:334495 | Mgi Id | MGI:7441762 |
| Doi | 10.1016/j.metabol.2023.155516 | Citation | Park J, et al. (2023) Metformin-induced TTP mediates communication between Kupffer cells and hepatocytes to alleviate hepatic steatosis by regulating lipophagy and necroptosis. Metabolism 141:155516 |
| abstractText | 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-alpha 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. |
