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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 | Distribution of polycyclic aromatic hydrocarbons in marine sediments and their potential toxic effects显示文摘 | Froehner S Maceno M Luz E C D | 2010 | Environmental Monitoring and Assessment2010，168，14： | 1 |
| 3 | Meeting browsing state-of-the- art review显示文摘 | Bouamrane M M and Luz S | 2007 | Multimedia Systems2007，12，45： | 1 |
| 4 | Struc-tural characterization of coagulant Moringa oera Lectin and its effect on hemostatic param- eters显示文摘 | Luz L A Silva M C Ferreira R S | 2013 | Int J Biol Macromol2013，58，： | 1 |
| 5 | On the transport properties in granular or weakl, coupled superconductors显示文摘 | C A M dos Santos M S da Luz B Ferreira | 2003 | Physica C2003，391，： | 1 |
| 6 | Cellulose and cellulignin from sugarcane bagasse reinforced polypropylene composites: Effect of acetylation on mechanical and thermal properties 显示文摘 | Luz S M Tio I D Rocha G I M | 2008 | Composites Part A: Applied Science and Manufacturing2008，39，9： | 1 |
| 7 | Improvements in the statistical approach to random Lévy flight searches显示文摘 | da Luz M G E Buldyrev S V Havlin S | 2001 | Physica A:Statistical Mechanics and Its Applications2001，295，12： | 1 |
| 8 | Thermal testing and numerical simulation of gypsum wallboards incorporated with different PCMs content显示文摘 | Borreguero A M Luz Sánchez M Valverde J L | 2011 | Applied Energy2011，88，3： | 1 |
| 9 | Mechanical behavior and microstructural analysis of sugarcane bagasse fibers reinforced polypropylene composites显示文摘 | S M Luz A R Goncalves A P Del'Arco Jr | | 0，，38： | 1 |
| 10 | Long-Term Changes in Game Species Over a Long Period of Transformation in the Iberian Mediterranean Landscape显示文摘 | Miguel Delibes-Mateos Miguel ángel Farfán Jesús Olivero Ana Luz Márquez Juan Mario Vargas | 2009 | Environmental Management2009，，6： | 1 |
| 11 | The transcription factor Gfi1regu-lates G-CSF signaling and neutrophil development through the Ras activator RasGRP1显示文摘 | DE LA LUZ SIERRA M SAKAKIBARA S GAS-PERINI P | 2010 | Blood2010，115，： | 1 |
| 12 | Clinicopathological correlation and prognostic significance of VEGFA,VEGF-C,VEGFR-2 and VEGFR-3 expression in colorectal cancer显示文摘 | Martins S F Garcia E A Luz M A | | 0，，2： | 1 |
| 13 | Endurance exercise training ameliorates insulin resistance and reticulum stress in adipose and hepatic tissue in obese rats显示文摘 | DA LUZ G FREDERICO M J S DA SILVA S | 2011 | Eur J Appl Physiol2011，111，9： | 1 |
| 14 | Cardiac tamponade associated with umbilical venous catheter (UVC) placed in inappropriate position显示文摘 | Gfilvez-Cancino F de la Luz S~lnchez-Tirado M | 2015 | Gac Med Mex2015，3，151： | 1 |
| 15 | Diabetogenic effects and pancreatic oxidative damage in rats subchronically exposed to arsenic显示文摘 | Luz M Claudia A S Luz C S | 2006 | Toxicology Letters2006，160，2： | 1 |
| 16 | Alkali activation of metakaolins: parameters affecting mechanic'd, structural and microstructural properties显示文摘 | Luz G M Blanco-Varela M T Martinez-Ramirez S | 2007 | Journal of Materials Science2007，429，： | 1 |
| 17 | Cellulose and cellulignin from sugarcane bagasse reinforced polypropylene composites:Effect of acetylation on mechanical and thermal properties显示文摘 | LUZ S M DEL TIO J R CHA G J M | 2008 | Composites Part A:Applied Science and Manufacturing2008，39，9： | 1 |
| 18 | International merger policy coordination显示文摘 | Cabral Luz's M B | 2003 | Japan and the World Economy2003，15，： | 1 |
| 19 | An equilibrium approach to international merger policy显示文摘 | Luz's M B Cabral | 2005 | International Journal of Industrial Organization2005，23，： | 1 |
| 20 | Reversion of steatosis by SREBP-1c antisense oligonucleotide did not improve hepatic insulin action in diet-induced obesity mice显示文摘 | Vitto M F Luz G Luciano T F Marques S O Souza D R Pinho R A Lira F S Cintra D E Desouza C T | | 0，，12： | 1 |
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