文献类型：期刊文献

英文题名：Hepatic stellate cell-specific Kcnma1 deletion mitigates metabolic dysfunction-associated steatotic liver disease progression via upregulating Amphiregulin secretion

作者：Zou, Yunhan[1,2];Wu, Jiaoxiang[3,4];Cheng, Sheng[3,4];Cheng, Daqing[3];Chen, Taoying[5];Guo, Xirong[4];Tang, Li[6];Su, Xianbin[7];Zhang, Man[7];Zhang, Xin[8];Liu, Ying[9];Zhang, Jin[3];Bao, Qun[3];Hou, Shangwei[4];Sun, Peng[3];Li, Yong[1,2];Han, Bo[3,4]

第一作者：Zou, Yunhan

通信作者：Li, Y[1];Li, Y[2];Sun, P[3];Han, B[3];Hou, SW[4];Han, B[4]

机构：[1]Shanghai Jiao Tong Univ, Tongren Hosp, Hongqiao Int Inst Med, Sch Med, Shanghai 200025, Peoples R China;[2]Shanghai Jiao Tong Univ, Fac Basic Med, Dept Biochem & Mol Cell Biol, Shanghai Key Lab Tumor Microenvironm & Inflammat,S, Shanghai 200025, Peoples R China;[3]Shanghai Jiao Tong Univ, Tongren Hosp, Dept Gen Surg, Sch Med, Shanghai, Peoples R China;[4]Shanghai Jiao Tong Univ, Tongren Hosp, Hongqiao Int Inst Med, Key Lab Translat Res & Innovat Therapeut Gastroint, Shanghai 200336, Peoples R China;[5]Guiyang Univ, Sch Food Sci & Engn, Guiyang 550005, Guizhou, Peoples R China;[6]Shanghai Jiao Tong Univ, Tongren Hosp, Rehabil Dept, Sch Med, Shanghai 200336, Peoples R China;[7]Shanghai Jiao Tong Univ, Shanghai Ctr Syst Biomed, Key Lab Syst Biomed, Minist Educ, Shanghai 200240, Peoples R China;[8]Shanghai Jiao Tong Univ, Natl Ctr Translat Med Shanghai, Inst Translat Med, Shanghai 200240, Peoples R China;[9]Gansu Univ Chinese Med, Clin Coll Tradit Chinese Med, Lanzhou 730000, Peoples R China

第一机构：Shanghai Jiao Tong Univ, Tongren Hosp, Hongqiao Int Inst Med, Sch Med, Shanghai 200025, Peoples R China

通信机构：[1]corresponding author), Shanghai Jiao Tong Univ, Tongren Hosp, Hongqiao Int Inst Med, Sch Med, Shanghai 200025, Peoples R China;[2]corresponding author), Shanghai Jiao Tong Univ, Fac Basic Med, Dept Biochem & Mol Cell Biol, Shanghai Key Lab Tumor Microenvironm & Inflammat,S, Shanghai 200025, Peoples R China;[3]corresponding author), Shanghai Jiao Tong Univ, Tongren Hosp, Dept Gen Surg, Sch Med, Shanghai, Peoples R China;[4]corresponding author), Shanghai Jiao Tong Univ, Tongren Hosp, Hongqiao Int Inst Med, Key Lab Translat Res & Innovat Therapeut Gastroint, Shanghai 200336, Peoples R China.

年份：2025

卷号：97

外文期刊名：MOLECULAR METABOLISM

收录：;Scopus(收录号：2-s2.0-105004998959);WOS:【SCI-EXPANDED(收录号:WOS:001493076500001)】；

基金：This work was supported by 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) .

语种：英文

外文关键词：KCNMA1; MASLD; HSCs; Lipid accumulation; AREG

摘要：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/).