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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 | Alginate hydrogels as synthetic extraeellular matrix materials 显示文摘 | Jon A R Gerard M Mooney D J | 1999 | Biomaterials1999，20，： | 1 |
| 3 | 显示文摘 | Jon A R Gerard M | 1999 | Biomaterials1999，20，： | 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 | Low voltage ride through of wind farms with cage generators: STATCOM versus SVC显示文摘 | Marta M Jon A S Tore U | 2008 | IEEE Trans on Power Electonics2008，23，3： | 1 |
| 6 | Gold Nannoparticle Patterning of Silicon Wafers Using Chemical e-Beam Lithography显示文摘 | Paula M Mendes Jon A Preece | 2004 | Langmuir2004，，20： | 1 |
| 7 | A method for creating chromosome-spe cific plasmid libraries enriched inclones containingn microsatellite repeat sequences directly from flowsorted chromosomes显示文摘 | Jon E W Graeme M B Robert A F | 1993 | Nucleic Acids Research1993，21，19： | 1 |
| 8 | 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 |
| 9 | Reduction of morning blood pressure surge after treatment with nifedipine GITS at bedtime,but not upon awakening,in essential hypertension显示文摘 | Hermida RC Ayala DE Mójon A | 2009 | Blood Pressure Monitoring2009，14，4： | 1 |
| 10 | Gold nanoparticle patterning of silicon wafers using chemical e-beam lithography显示文摘 | Mendes Paula M Preece Jon A | 2004 | Langmuir2004，20，9： | 1 |
| 11 | An information retrieval approach to ontology mapping 显示文摘 | SU X M JON A G | 2006 | Data & Knowledge Engineering2006，58，1： | 1 |
| 12 | The effect of endurance training on parameters of aerobic fitness显示文摘 | Jons A M Cater H | | 0，，01： | 1 |
| 13 | High presynapticdopaminergic activity in children with Tourette's disorder显示文摘 | ERNST M ZAMETKIN A J JONS P H | 1999 | J Am Acad Child Adolesc Psychiatry1999，38，1： | 1 |
| 14 | 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 |
| 15 | 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 |
| 16 | 显示文摘 | Philip L H Barry L J Gary O M Paul L A Jon M Moore | 1999 | Journal of Power Sources1999，80，： | 1 |
| 17 | Low voltage ride through of wind farms with cage generators: STATCOM versus SVC 显示文摘 | MOLINAS M JON A S | 2008 | IEEE Transactions on Power Electronics2008，23，3： | 1 |
| 18 | Elevated CO2 reduces the drought effect on nitrogen metabolism in barley plants during drought and subsequent recovery 显示文摘 | Robredo A Usue P L Jon M A Lacuesta M Amaia M P Alberto M R | 2011 | Environmental and Experimental Botany2011，71，3： | 1 |
| 19 | Side- by-side comparison of nitrogen species removal for four types of permeable pavement and standard asphalt in eastern North Carolina 显示文摘 | Collins Kelly A Hunt William F Hathaway Jon M | 2009 | J Hydro1 Eng2009，15，6： | 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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