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

Authors
Park, J.Rah, S.-Y.An, H.S.Lee, J.Y.Roh, G.S.Ryter, S.W.Park, J.W.Yang, C.H.Surh, Y.-J.Kim, U.-H.Chung, H.T.Joe, Y.
Issue Date
Apr-2023
Publisher
W.B. Saunders
Keywords
Hepatocytes; Kupffer cells; Lipophagy; Metformin; Necroptosis; Non-alcoholic fatty liver disease; Sirt1; Tristetraprolin
Citation
Metabolism: Clinical and Experimental, v.141
Indexed
SCIE
SCOPUS
Journal Title
Metabolism: Clinical and Experimental
Volume
141
URI
https://scholarworks.gnu.ac.kr/handle/sw.gnu/30152
DOI
10.1016/j.metabol.2023.155516
ISSN
0026-0495
1532-8600
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. © 2023
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