Arachidyl amido cholanoic acid improves liver glucose and lipid homeostasis in nonalcoholic steatohepatitis via AMPK and mTOR regulation  

作　　者：David Fernández-Ramos Fernando Lopitz-Otsoa Laura Delacruz-Villar Jon Bilbao Martina Pagano Laura Mosca Maider Bizkarguenaga Marina Serrano-Macia Mikel Azkargorta Marta Iruarrizaga-Lejarreta Jesús Sot Darya Tsvirkun Sebastiaan Martijn van Liempd Felix M Goni Cristina Alonso María Luz Martínez-Chantar Felix Elortza Liat Hayardeny Shelly C Lu JoséM Mato 

机构地区：[1]Precision Medicine and Metabolism Laboratory,Centro de Investigación Cooperativa en Biociencias(CIC bioGUNE),Derio 48160,Bizkaia,Spain [2]CIBERehd-Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas,Madrid 28029,Spain [3]Department of Precision Medicine,University of Campania"Luigi Vanvitelli",Naples 80138,Italy [4]Liver Disease Laboratory,Centro de Investigación Cooperativa en Biociencias(CIC bioGUNE),Derio 48160,Spain [5]Proteomics Platform,Centro de Investigación Cooperativa en Biociencias(CIC bioGUNE),Derio 48160,Spain [6]OWL Metabolomics,Derio 48160,Spain [7]Instituto Biofisika(UPV/EHU,CSIC),Leioa 48940,Spain,Departamento de Bioquímica y Biología Molecular,Universidad del País Vasco,Leioa 48940,Spain [8]Pre-clinical and Chemistry,Manufacturing and Controls,Galmed Pharmaceuticals,Tel Aviv 6578317,Israel [9]Metabolomics Platform,Centro de Investigación Cooperativa en Biociencias(CIC bioGUNE),Derio 48160,Spain [10]Division of Digestive and Liver Diseases,Cedars-Sinai Medical Center,Los Angeles,CA 90048,United States

出　　处：《World Journal of Gastroenterology》2020年第34期5101-5117,共17页世界胃肠病学杂志（英文版）

基　　金：National Institutes of Health Grant,No.R01CA172086;Plan Nacional of I+D,No.SAF2017-88041-R;Ministerio de Economía y Competitividad de España,No.SAF2017-87301-R;Asociación Española contra el Cáncer,No.AECC17/302;Ayudas Fundación BBVA a equipos de Investigación Científica 2018;Fondo Europeo de Desarrollo Regional,Ministerio de Economia y Competitividad de España,No.PGC2018-099857-BI00;Basque Government Grants,No.IT1264-19;Ministerio de Economia y Competitividad de España for the Severo Ochoa Excellence Accreditation,No.SEV-2016-0644.The funders had no role in study design,data collection and analysis,decision to publish,or preparation of the manuscript.

摘　　要：BACKGROUND Arachidyl amido cholanoic acid(Aramchol)is a potent downregulator of hepatic stearoyl-CoA desaturase 1(SCD1)protein expression that reduces liver triglycerides and fibrosis in animal models of steatohepatitis.In a phase IIb clinical trial in patients with nonalcoholic steatohepatitis(NASH),52 wk of treatment with Aramchol reduced blood levels of glycated hemoglobin A1c,an indicator of glycemic control.AIM To assess lipid and glucose metabolism in mouse hepatocytes and in a NASH mouse model[induced with a 0.1%methionine and choline deficient diet(0.1MCD)]after treatment with Aramchol.METHODS Isolated primary mouse hepatocytes were incubated with 20μmol/L Aramchol or vehicle for 48 h.Subsequently,analyses were performed including Western blot,proteomics by mass spectrometry,and fluxomic analysis with 13C-uniformly labeled glucose.For the in vivo part of the study,male C57BL/6J mice were randomly fed a control or 0.1MCD for 4 wk and received 1 or 5 mg/kg/d Aramchol or vehicle by intragastric gavage for the last 2 wk.Liver metabolomics were assessed using ultra-high-performance liquid chromatography-time of flight-MS for the determination of glucose metabolism-related metabolites.RESULTS Combination of proteomics and Western blot analyses showed increased AMPK activity while the activity of nutrient sensor mTORC1 was decreased by Aramchol in hepatocytes.This translated into changes in the content of their downstream targets including proteins involved in fatty acid(FA)synthesis and oxidation[PACCα/β(S79),SCD1,CPT1A/B,HADHA,and HADHB],oxidative phosphorylation(NDUFA9,NDUFB11,NDUFS1,NDUFV1,ETFDH,and UQCRC2),tricarboxylic acid(TCA)cycle(MDH2,SUCLA2,and SUCLG2),and ribosome(P-p70S6K[T389]and P-S6[S235/S236]).Flux experiments with 13Cuniformely labeled glucose showed that TCA cycle cataplerosis was reduced by Aramchol in hepatocytes,as indicated by the increase in the number of rounds that malate remained in the TCA cycle.Finally,liver metabolomic analysis showed that glucose homeostasis was improved by Aram

关 键 词：Nonalcoholic fatty liver disease STEATOHEPATITIS Methionine and choline deficient diet Tricarboxylic acid cycle Hemoglobin A1c Stearoyl-CoA desaturase 1 

分 类 号：R575.5[医药卫生—消化系统]