Co-administration of ursodeoxycholic acid with rosuvastatin/ezetimibe in a non-alcoholic fatty liver disease model

查看全文 作　　者：Sang Hyun [1,2]Seo;Da Hyun [3,4]Lee;Yu Seol [3,4]Lee;Kyung Joo [1,2]Cho;Hye Jung [2]Park;Hye Won [2,5]Lee;Beom Kyung [2,5]Kim;Jun Yong [2,5]Park;Do Young [2,5]Kim;Sang Hoon [2,5]Ahn;Soo Han [3,4]Bae;Seung Up [2,5]Kim 机构地区：[1]Department of Internal Medicine,Graduate School of Medicine Science,Brain Korea 21 Project,Yonsei University College of Medicine,Seoul,Republic of Korea;[2]Yonsei Liver Center,Severance Hospital,Seoul,Republic of Korea;[3]Severance Biomedical Science Institute,Graduate School of Medical Science,Brain Korea 21 Project,Yonsei University College of Medicine,Seoul,Republic of Korea;[4]Severance Biomedical Science Institute,Yonsei Biomedical Research Institute,Yonsei University College of Medicine,Seoul,Republic of Korea;[5]Department of Internal Medicine,Institute of Gastroenterology,Yonsei University College of Medicine,Seoul,Republic of Korea 出　　处：《Gastroenterology Report》索引2022年第10卷第1期,共11页 基　　金：supported by Daewoong Pharmaceutical company,and was supported by a Faculty Research Grant from the Yonsei University College of Medicine(6-2019-0068 to S.H.Bae);by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI);funded by the Ministry of Health&Welfare,Republic of Korea(HI17C0913 and HI16C0257 to S.H.Bae);supported by the National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT)(NRF-2022R1A2C2003438 to S.H.Bae,NRF-2021R1C1C2095694 to D.H.Lee);by Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT&Future Planning(2019R1A2C4070136 to S.U.Kim). 摘　　要：Background Ursodeoxycholic acid(UDCA),statins,and ezetimibe(EZE)have demonstrated beneficial effects against nonalcoholic fatty liver disease(NAFLD).We investigated the efficacy of the combination of UDCA and the mix of rosuvastatin(RSV)/EZE in the treatment of NAFLD.Methods NAFLD mouse models were developed by injecting thioacetamide,fasting,and high-carbohydrate refeeding,highfat diet,and choline-deficient L-amino acid-defined high-fat diet(CDAHFD).Low-dose UDCA(L-UDCA;15 mg/kg)or highdose UDCA(H-UDCA;30 mg/kg)was administered with RSV/EZE.We also employed an in vitro model of NAFLD developed using palmitic acid-treated Hepa1c1c7 cells.Results Co-administration of RSV/EZE with UDCA significantly decreased the collagen accumulation,serum alanine aminotransferase(ALT)levels,and mRNA levels of fibrosis-related markers than those observed in the vehicle group in thioacetamide-treated mice(all P<0.01).In addition,in the group fasted and refed with a high-carbohydrate diet,UDCA/RSV/EZE treatment decreased the number of apoptotic cells and serum ALT levels compared with those observed in the vehicle group(all P<0.05).Subsequently,H-UDCA/RSV/EZE treatment decreased the number of ballooned hepatocytes and stearoyl-CoA desaturase 1(SCD-1)mRNA levels(P=0.027)in the liver of high-fat diet-fed mice compared with those observed in the vehicle group.In the CDAHFD-fed mouse model,UDCA/RSV/EZE significantly attenuated collagen accumulation and fibrosis-related markers compared to those observed in the vehicle group(all P<0.05).In addition,UDCA/RSV/EZE treatment significantly restored cell survival and decreased the protein levels of apoptosis-related markers compared to RSV/EZE treatment in palmitic acid-treated Hepa1c1c7 cells(all P<0.05).Conclusion Combination therapy involving UDCA and RSV/EZE may be a novel strategy for potent inhibition of NAFLD progression. 关 键 词：non-alcoholic fatty liver disease non-alcoholic steatohepatitis ursodeoxycholic acid ROSUVASTATIN EZETIMIBE