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

Autor: Park J; School of Biological Sciences, University of Ulsan, Ulsan 44610, Republic of Korea., Rah SY; National Creative Research Laboratory for Ca(2+) signaling Network, Chonbuk National University Medical School, Jeonju 54907, Republic of Korea., An HS; Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea., Lee JY; Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea., Roh GS; Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea., Ryter SW; Proterris Inc., Boston, MA 02118, USA., Park JW; School of Biological Sciences, University of Ulsan, Ulsan 44610, Republic of Korea., Yang CH; College of Korean Medicine, Daegu Haany University, Daegu 42158, Republic of Korea., Surh YJ; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea; Cancer Research Institute, Seoul National University, Seoul 03080, Republic of Korea., Kim UH; Department of Biochemistry, School of Medicine, Wonkwang University, Iksan 54538, Republic of Korea., Chung HT; School of Biological Sciences, University of Ulsan, Ulsan 44610, Republic of Korea. Electronic address: chung@ulsan.ac.kr., Joe Y; School of Biological Sciences, University of Ulsan, Ulsan 44610, Republic of Korea. Electronic address: jcantibody@ulsan.ac.kr.
Jazyk: angličtina
Zdroj: Metabolism: clinical and experimental [Metabolism] 2023 Apr; Vol. 141, pp. 155516. Date of Electronic Publication: 2023 Feb 10.
DOI: 10.1016/j.metabol.2023.155516
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare no conflicts of interest.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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