Adipose ADM2 ameliorates NAFLD via promotion of ceramide catabolism  

作　　者：Pengcheng Wang Song-Yang Zhang YongQiang Dong Guangyi Zeng Huiying Liu Xian Wang Changtao Jiang Yin Li 

机构地区：[1]Center of Basic Medical Research,Institute of Medical Innovation and Research,Third Hospital,Peking University,Beijing 100191,China [2]Department of Immunology,School of Basic Medical Sciences,NHC Key Laboratory of Medical Immunology,Peking University,Beijing 100191,China [3]The First Affiliated Hospital of Zhengzhou University,Zhengzhou University,Zhengzhou 450052,China [4]Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Peking University,State Key Laboratory of Vascular Homeostasis and Remodeling,Beijing 100191,China [5]Department of Integration of Chinese and Western Medicine,School of Basic Medical Sciences,Peking University,Tasly Microcirculation Research Center,Peking University Health Science Center,Beijing 100191,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第11期4883-4898,共16页药学学报（英文版）

基　　金：National Key Research and Development Program of China(Nos.2020YFA0803801,2022YFA0806400,and 2018YFA0800701);National Natural Science Foundation of China(Nos.81921001 and 32200949);project funded by China Postdoctoral Science Foundation(BX20220021,China);Xin Du and Julian Heng(Remotely Consulting,Australia)provided professional English-language editing of this article(Certificate No.2Tv2Ry7I).

摘　　要：The adipose tissue of mammals represents an important energy-storing and endocrine organ, and its dysfunction is relevant to the onset of several health problems, including non-alcoholic fatty liver disease (NAFLD). However, whether treatments targeting adipose dysfunction could alleviate NAFLD has not been well-studied. Adrenomedullin 2 (ADM2), belonging to the CGRP superfamily, is a protective peptide that has been shown to inhibit adipose dysfunction. To investigate the adipose tissue-specific effects of ADM2 on NAFLD, adipose-specific ADM2-overexpressing transgenic (aADM2-tg) mice were developed. When fed a high-fat diet, aADM2-tg mice displayed decreased hepatic triglyceride accumulation compared to wild-type mice, which was attributable to the inhibition of hepatic de novo lipogenesis. Results from lipidomics studies showed that ADM2 decreased ceramide levels in adipocytes through the upregulation of ACER2, which catalyzes ceramide catabolism. Mechanically, activation of adipocyte HIF2α was required for ADM2 to promote ACER2-dependent adipose ceramide catabolism as well as to decrease hepatic lipid accumulation. This study highlights the role of ADM2 and adipose-derived ceramide in NAFLD and suggests that its therapeutic targeting could alleviate disease symptoms.

关 键 词：Non-alcoholicfatty liver disease Adiposetissue Lipid metabolism Adrenomedullin 2 CERAMIDE HIF2α ACER2 

分 类 号：R575[医药卫生—消化系统]