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| 1 | Arachidyl amido cholanoic acid improves liver glucose and lipid homeostasis in nonalcoholic steatohepatitis via AMPK and mTOR regulation显示文摘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 Aramchol in 0.1MCD fed mice in a dose-dependent manner,showing normalization of glucose,G6P,F6P,UDP-glucose,and Rbl5P/Xyl5P.CONCLUSION Aramchol exerts its effect on glucose and lipid metabolism in NASH through activation of AMPK and inhibition of mTORC1,which in turn activate FAβ-oxidation and oxidative phosphorylation. | 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 | 2020 | World Journal of Gastroenterology2020，26，34： | 5 |
| 2 | 48th Annual Meeting and ToxExpoTM显示文摘 | SOT | 2009 | The Toxicologist Supplement to Toxicological Sciences2009，108，1： | 1 |
| 3 | Observability of complete multipartite graphs with equipotent parts显示文摘 | HORNK M SOT K R | 1995 | Ars Com- binatoria1995，41，： | 1 |
| 4 | Genetic variation analysis of 15 autosomal STR loci in Eastern Slovak Caucasian and Romany(Gypsy)population显示文摘 | Soták M Petrejcíková E Bemasovská J | | 0，，01： | 1 |
| 5 | Asymptotic behavior of the observability of Q n 显示文摘 | HORNK M SOT K R | 1997 | Discrete Mathematics1997，176，： | 1 |
| 6 | Observability of a graph显示文摘 | Horňák M Soták R | 1996 | Math Slovaca1996，，46： | 1 |
| 7 | Localization jumps of the point-distinguishing chromatic index of K n,n 显示文摘 | HORNK M SOT K R | 1997 | Discuss Math Graph Theory1997，17，： | 1 |
| 8 | Asymptotic behaviour of the observability of Qn显示文摘 | Soták R | 1997 | Discrete Mathematics1997，，176： | 1 |
| 9 | A method for estimating primary pro- duction from chlorophyll concentrations with results showing trends in the Irish Sea and the Dutch coastal zone显示文摘 | ]Sot P Colijn F | 1996 | ICES Journal of Marine Science1996，53，6： | 1 |
| 10 | Integrating reliability,availability,maintainability and supportability with risk analysis for improved operation of the Afam thermal power-station显示文摘 | Eti MC Ogaji SOT Probert SD | 2007 | APPLIED ENERGY2007，84，： | 1 |
| 11 | Biophysical properties of sphingosine,ceramidesand other simple sphingolipids 显示文摘 | Goni FM Sot J Alonso A | 2014 | Biochem Soc Trans2014，42，5： | 1 |
| 12 | Reducing the cost of preventive maintenance(PM)through adopting a proactive reliability focused culture显示文摘 | Eti MC Ogaji SOT Probert SD | 2006 | APPLIED ENERGY2006，83，： | 1 |
| 13 | Oxidative dimerization of aromatic amines using t-BuOI:Entry to unsymmet- tic aromatic azo compounds 显示文摘 | Youhei T Sots O Satoshi M | 2012 | Angewandte Che- mie2012，124，31： | 1 |
| 14 | Claudin and p53 expression in vulvar lichen sclerosus and squamous-cell carcinoma显示文摘 | SadaUa JC Lourenco SV Sot'to MN | 2011 | J Clin Pathol2011，64，10： | 1 |
| 15 | Arbitrarilylargedifferencebetweend-strongchromaticindexanditstriviallowerbound显示文摘 | MockovˇciakváM SotákR | 2013 | DiscreteMath2013，313，19： | 1 |
| 16 | Malignant hilar and biliary obstruction: Use of MR cholangiography to define the biliary ductal involvement and plan percutaneous interventions显示文摘 | perihilar extent of Radiology Lopera JE Sot o JA M nera F | 2001 | 220(1):90-962001，220，1： | 1 |
| 17 | Asympotic behaviour of the observability of Qn 显示文摘 | Hornák P N Soták R | 1997 | Discrete Mathematics1997，176，： | 1 |
| 18 | Factors affecting Sihomoeyst einylation of LDL apoprot ein B 显示文摘 | Zinellu A Zinellu E Sot gia S | 2006 | Clin Chem2006，52，11： | 1 |
| 19 | A case study of coupling between low and upper level jet front system: Investigation of dynamical and diabatic processes显示文摘 | SOT MS J L CAMMA J P YU X D | 1987 | Mon Wea Rew1987，121，8： | 1 |
| 20 | Is It Worth Continuing Sexual Rehabilitation af-ter Radical Prostatectomy with Intracavernous Injection of Al-prostadil for More than 1 Year? 显示文摘 | Ren Yiou MD PhD PUPH MD Zentia B tow MD JuliettePari sot* | 2014 | Sexual Medicine2014，3，1： | 1 |
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