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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 | An experimental investigation of the electrostatic discharge (ESD) mechanism in packaged semiconductor devices显示文摘 | M C Jon T L Welsher | 1994 | J of Electrostatics1994，32，： | 1 |
| 3 | Prior Family Business Exposure as lntergenerational Influence and Entrepreneurial Intent:a Theory of Planned Behavior Approach 显示文摘 | JON C C JENNIFER M S | 2007 | Journal of Busi- ness Research2007，60，10： | 1 |
| 4 | Recent advance in techniques for hyperspectral image processing显示文摘 | Antonio P Jon A B Joseph W B Jason B Lorenzo B Gustavo C V Jocelyn C Mathieu F Paolo G Anthony G Mattia M James C T Giovanna T | 2009 | Remote Sensing of Environment2009，113，： | 1 |
| 5 | Inhibition mechanism of kojic acid on polyphenol oxidase 显示文摘 | Jon S C Cheng W Marry R M | 1991 | Agricultural and Food Chemistry1991，39，11： | 1 |
| 6 | Pre-osteoblast infiltration and differentiation in highly porous apatite-coated PLLA electrospun scaffolds显示文摘 | BRYCE M Whited JON R Whitney MATTHIAS C Hofmann | 2011 | Biomaterials2011，，32： | 1 |
| 7 | Rationale for the use of optical mice chips for economic and accurate vehicle tracking 显示文摘 | JOSHUA D J DALE W C JON M A | 2007 | Automation Science Engineering2007，，9： | 1 |
| 8 | Experimental model of fungal sinusi tis~a pilot study in rabbits显示文摘 | DUFOUR X KAUFFMANN-LACROIX C GOU JON J M | 2005 | Ann Otol Rhinol Lar yngol2005，114，： | 1 |
| 9 | Experimental model of fungal sinusitis a pilot study in rabbits显示文摘 | DUFOUR X KAUFFMANN LACRO1X C GOU- JON J M | 2005 | Ann Otol Rhinol Laryngol2005，114，： | 1 |
| 10 | Long-term re- cording of cardiac arrhythmias with an implantable cardiac monitor in patients with reduced ejection fraction after acute myocardial in- farction: the Cardiac Arrhythmias and Risk Stratificatio-n After A- cute Myocardial Infarction ( CARISMA ) study 显示文摘 | Bloch Thomsen PE Jons C Raatikainen M J | 2010 | Circulation2010，122，13： | 1 |
| 11 | Proteomic identification of a novel protein regulated in CA1 and CA3 hippocampal regions during intermittent hypoxia显示文摘 | Jon B K David G William M P Visith T Janice A S Leroy R S Shang Z G Jian C Evelyne G | 2003 | Respir Physiol Neurobiol2003，136，： | 1 |
| 12 | Self-control relies on glucose as a limited energy source: willpower is more than a metaphor显示文摘 | Gailliot Matthew T Baumeister Roy F DeWall C Nathan Maner Jon K Plant E Ashby Tice Dianne M Brewer Lauren E Schmeichel Brandon J | 2007 | Journal of Personality and Social Psychology2007，92，2： | 1 |
| 13 | Current knowledge on groundwater microbial pathogens and their control显示文摘 | Bruce A M Jon C M | 2000 | Hydrogeology Journal2000，8，1： | 1 |
| 14 | Influence of dia- betes mellitus on inappropriate and appropriate implant- able cardioverter-defibrillator therapy and mortality in the Multicenter Automatic Defibrillator Implantation Trial-Re- duce Inappropriate Therapy (MADIT-RIT) Trial显示文摘 | Ruwald M H Zareba W Jons C | 2013 | Cir- culation2013，128，7： | 1 |
| 15 | Polybrominated diphenyl ether flame retardants in the North American environment 显示文摘 | Hale R C Alaee M Jon B | 2003 | Environment International2003，29，： | 1 |
| 16 | Syndecan-1 is the primary heparan sulfate proteoglycan mediating hepatic clearance of triglyceride-rich lipoproteins in mice显示文摘 | Stanford Kristin I Bishop Joseph R Foley Erin M Gonzales Jon C Niesman Ingrid R Witztum Joseph L Esko Jeffrey D | 2009 | Journal of Clinical Investigation2009，，11： | 1 |
| 17 | A practical approach to the design of robust speed controllers for machine drives显示文摘 | Hakan Akpolat Z Greg M Asher Jon C Clare | 2000 | IEEE Transactions on Industrial Electronics2000，47，2： | 1 |
| 18 | Speed-profile model for two-lane rural highways 显示文摘 | Kay F Jon M C | 2000 | Joural of the Transportation Research Board2000，1737，6： | 1 |
| 19 | Electrostatic Discharge Failure Mechanism for Cordless Phone Charge Contacts 显示文摘 | COYLE R J JON M C | 2000 | Journal of Electrostatics2000，49，： | 1 |
| 20 | Pharmacological and immunochemical characterization of α2* nicotinic acetylcholine receptors (nAChRs) in mouse brain显示文摘 | Paul WHITEAKER Jennifer A WILKING Robert WB BROWN Robert J BRENNAN Allan C COLLINS Jon M LINDSTROM Jim BOULTER | 2009 | Acta Pharmacologica Sinica2009，30，6： | 1 |
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