Repurposing lansoprazole to alleviate metabolic syndrome via PHOSPHO1 inhibition  

作　　者：Yingting Wu Jiaqi Xin Xinyu Li Ting Yang Yi Liu Yongsheng Zhao Wen Xie Mengxi Jiang 

机构地区：[1]Department of Pharmacology,School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China [2]Department of Traditional Chinese Medicine,Capital Medical University,Beijing 100069,China [3]Center for Pharmacogenetics and Department of Pharmaceutical Sciences,University of Pittsburgh,Pittsburgh,PA 15261,USA [4]Advanced Innovation Center for Human Brain Protection,Capital Medical University,Beijing 100069,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第4期1711-1725,共15页药学学报（英文版）

基　　金：This work was supported by the Beijing Municipal Natural Science Foundation Grant 7212148(to Mengxi Jiang,China);the National Natural Science Foundation of China Grant 82000807(to Mengxi Jiang,China);the Beijing Municipal Education Commission Grant KM202110025023(to Mengxi Jiang,China).

摘　　要：Drug repurposing offers an efficient approach to therapeutic development.In this study,our bioinformatic analysis first predicted an association between obesity and lansoprazole(LPZ),a commonly prescribed drug for gastrointestinal ulcers.We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity,insulin resistance,and hepatic stea-tosis in mice.Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes,and induced cold tolerance in cold-exposed mice,suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism.Mechanistically,LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1(PHOSPHOI)and produces metabolic benefits in a PHOS-PHO1-dependent manner.Our results suggested that LPZ may stimulate adipose thermogenesis by inhi-biting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid(2-AG-LPA)to 2-arachidonoylglycerol(2-AG)and reduce the activity of the thermogenic-suppressive cannabinoid recep-tor signaling.In summary,we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome,and identified a potential metabolic basis by which LPZ improves energy metabolism.

关 键 词：LANSOPRAZOLE Proton pump inhibitors Adipose thermogenesis Energy expenditure Metabolic syndrome PHOSPHO1 inhibitor Cannabinoid receptor signaling Drug repurposing 

分 类 号：R96[医药卫生—药理学]