机构：[1]Hongqiao International Institute of Medicine, Tongren Hospital and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China[2]Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China[3]Key Laboratory for Translational Research and Innovative Therapeutics of Gastrointestinal Oncology, Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China[4]School of Food Science and Engineering, Guiyang University, Guizhou, 550005, China[5]Rehabilitation Department, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200336, China[6]Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China[7]Institute of Translational Medicine, National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China[8]Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, 730000, China
Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health concern, with limited effective treatments. KCNMA1 potassium channel has been implicated in the pathogenesis of various metabolic diseases. However, whether and how KCNMA1 regulates MASLD have been elusive. Methods: Global, hepatic stellate cells (HSCs)-specific, and hepatocyte-specific Kcnma1 knockout mice were fed either a standard chow or a high-fat diet (HFD). Serum and liver tissues were collected and analyzed by biochemical assay, histology, qPCR and western blotting. HSCs conditioned medium (CM) treatment hepatocytes experiment model and three-dimensional (3D) hepatocytes-HSCs spheroids were employed to study lipid accumulation in hepatocytes. A Cytokine Antibody Array was used to analyze the cytokine profile. Results: Our study demonstrated that global Kcnma1 deletion prevented diet-induced hepatic steatosis and improved insulin sensitivity. Further analyses using HSC-specific and hepatocyte-specific Kcnma1 knockout MASLD mouse models revealed that the protective effect against hepatic steatosis was predominantly mediated by Kcnma1 deletion in HSCs, rather than in hepatocytes. CM transfer experiment and 3D spheroid studies show Kcnma1 deletion effectively prevents lipid accumulation in hepatocytes. Mechanically, Kcnma1-deficient HSCs secrete Amphiregulin (AREG) to regulate lipid metabolism in hepatocytes via epidermal growth factor receptor (EGFR) signaling. Of clinical significance, AREG levels were notably reduced in the liver tissue of MASLD patients, while injection of recombinant AREG protein significantly ameliorated MASLD in mice. Conclusions: Our study uncovers a novel mechanism in which Kcnma1 deletion in HSCs enhances AREG secretion, thereby reducing lipid accumulation in hepatocytes through the AREG/EGFR signaling, ultimately inhibiting the progression of MASLD. (c) 2025 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
基金：
National Natural Science Foundation of
China (82070634, 82300971, 82002495), National Key Research and
Development Program of China (2021YFC2701900), Shanghai Jiao
Tong University Cross Disciplinary Translational Foundation
(YG2022QN117, YG2022QN116), Research Fund of Shanghai Tongren Hospital (TRKYRC-xx202205, TRKYRC-xx202212, TRKYRC-xx202213),
and Natural Science Foundation of Shanghai Municipality
(23ZR1458200).
第一作者机构：[1]Hongqiao International Institute of Medicine, Tongren Hospital and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
共同第一作者：
通讯作者：
通讯机构：[2]Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China[3]Key Laboratory for Translational Research and Innovative Therapeutics of Gastrointestinal Oncology, Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China
医学