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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 | Effect of somatostatin on mensenteric vascular resistance in normal dan portal hypertenstion rats显示文摘 | Sieber C Mosca P G Groszmann R J | 1992 | Am J Physiol1992，262，： | 1 |
| 3 | Pushing structoral information into the yeast interactome by high-throughput protein docking experiments 显示文摘 | Mosca R Pons C Fernmdez-Recio J | 2009 | PLoS Comput Biol2009，5，10： | 1 |
| 4 | Comparison of corneal aberration changes after laser in situ keratomileusis performed with mechanical microkeratome and IntraLase femtosecond laser:1-year follow-up显示文摘 | Buzzonetti L Petrocelli G Valente P Tamburrelli C Mosca L Laborante A | | 0，，2： | 1 |
| 5 | Talipes equinovarus and maternal smoking: a population-based case-control study in Washington state显示文摘 | SKELLY A C HOLT V L MOSCA V S etal | 2002 | J Teratol2002，66，2： | 1 |
| 6 | HbAlc stan- dardisation : history, science and politics 显示文摘 | John WG Mosca A Weykamp C | 2007 | Clin Biochem Rev2007，28，4： | 1 |
| 7 | Evidence-based guidelines for cardiovascular disease prevention in women:2007 up-date 显示文摘 | Mosca L Banka C L Emelia J | 2007 | Circulation2007，115，11： | 1 |
| 8 | Human mesenchymal stem cells respond to fibroblast growth factors显示文摘 | Mosca JD Winkles J | 1997 | Hum Cell1997，10，： | 1 |
| 9 | The IFCC reference meas- urement system for HbAlc: a 6-year progress report 显示文摘 | Weykamp C John WG Mosca A | 2008 | Clin Chem2008，54，2： | 1 |
| 10 | Undifferentiated connective tissue diseases (UCTD)显示文摘 | Mosca M Tani C Neri C | 2006 | Autoimmun Rev2006，6，1： | 1 |
| 11 | Assessment of patients with systemic lupus erythematosus and the use of lupus disease activity indices显示文摘 | Griffiths B Mosca M Gordon C | | 0，，： | 1 |
| 12 | Cap- saicin-induced apoptosis of glioma cells is mediated by TRPVI vanilloid receptor and requires p38 MAPK activation 显示文摘 | AMANTINI C MOSCA M NABISSI M | 2007 | J Neurochem2007，102，3： | 1 |
| 13 | A review of the challenge in measuring hemoglobin Alc显示文摘 | Weykamp C John WG Mosca A | 2009 | J Diabetes Sci Technol2009，3，3： | 1 |
| 14 | Undifferentiated connective tissue diseases in 2004显示文摘 | Mosca M Baldini C Bombatdieri S | | 0，，： | 1 |
| 15 | Effect of somatostatin on mesenteric vascular resistance in normal and portal hypertension rats显示文摘 | Sieber C Mosca PG Groszmann RJ | 1992 | Am J Physiol1992，262，21： | 1 |
| 16 | Effect of gel texture and sucrose spatial distribution on sweetness perception显示文摘 | MOSCA A C VELDE F BULT J H F | | 0，，01： | 1 |
| 17 | Monoclonal antibodies reactive with human osteogenic cell surface antigens显示文摘 | Bruder S P Horowitz M C Mosca J D | 1997 | Bone1997，21，3： | 1 |
| 18 | Assessment of patients with sys- temic lupus erythematosus and the use of lupus disease activity in- dices 显示文摘 | Griffiths B Mosca M Gordon C | 2005 | Best Pract Res Clin Rheumatol2005，19，5： | 1 |
| 19 | 冠心病和其他动脉粥样硬化性血管疾病二级预防指南:2006年版(摘要)显示文摘美国心脏学会(American College of Cardiology,ACC)与美国心脏病协会(American Heart Association.AHA)关于二级预防的共识声明自2001年更新以来,许多临床试验提供了重要证据.进一步支持和拓展了对冠心病和其他动脉粥样硬化性血管疾病(包括外周动脉疾病、动脉粥样硬化性主动脉疾病和颈动脉疾病)进行积极控制危险因素治疗的重要性。证据不断涌现,证实对这些患者进行积极而全面的危险因素干预治疗能够改善生存率,减少事件复发以及对介入治疗的需要.并提高生活质量。 | SMITH S C ALLEN J BLAIR S N BONOW R O BRASS L M FONAROW G C GRUNDY S M HIRATZKA L JONES D KRUMHOLZ H M MOSCA L PASTERNAK R C PEARSON T PFEFFER M A TAUBERT K A | 2008 | 岭南心血管病杂志2008，14，2： | 1 |
| 20 | Multilineage potential of adult human mesenchymal stem cells显示文摘 | Pittenger M F Mackay A M Beck S C Jaiswal R K Douglas R Mosca J D | 1999 | Science1999，284，： | 1 |
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