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울산대학교

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Metab.-Clin. Exp., 2023 Apr;141:155516 | https://doi.org/10.1016/j.metabol.2023.155516 Metformin-induced TTP mediates communication between Kupffer cells and hepatocytes to alleviate hepatic steatosis by regulating lipophagy and necroptosis

Jeongmin Park ^a, So-Young Rah ^b, Hyeong Seok An ^c, Jong Youl Lee ^c, Gu Seob Roh ^c, Stefan W. Ryter ^d, Jeong Woo Park ^a, Chae Ha Yang ^e, Young-Joon Surh ^f,g, Uh-Hyun Kim^h, Hun Taeg Chung ^a, Yeonsoo Joe ^a

^aSchool of Biological Sciences, University of Ulsan, Ulsan 44610, Republic of Korea
^bNational Creative Research Laboratory for Ca2+ signaling Network, Chonbuk National University Medical School, Jeonju 54907, Republic of Korea
^cDepartment of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju 52727, Republic of Korea
^dProterris Inc., Boston, MA 02118, USA
^eCollege of Korean Medicine, Daegu Haany University, Daegu 42158, Republic of Korea
^fDepartment of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea
^gCancer Research Institute, Seoul National University, Seoul 03080, Republic of Korea
^hDepartment of Biochemistry, School of Medicine, Wonkwang University, Iksan 54538, Republic of Korea

Corresponding authors: Hun Taeg Chung, Yeonsoo Joe

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.

논문정보

형식Research article
게재일2023년 04월 (BRIC 등록일 2023-04-13)
연구진국내(교신)+국외 연구진
분야 생명과학 > 노화/암생물학

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