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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 | Oxidative stress in apoptosis and cancer: an update显示文摘 | José M. Matés Juan A. Segura Francisco J. Alonso Javier Márquez | 2012 | Archives of Toxicology2012，，11： | 2 |
| 3 | Determinants of Release Rate of Tetanus Vaccine from Polyester Microspheres显示文摘 | ALONSO M J COHEN S PARK T G | 1993 | Pharm Res1993，10，： | 1 |
| 4 | Biogenic amine production by Oenococcus oeni isolates from malolactic fermentation of Tempranillo wine显示文摘 | IZQUIERDO-CANAS P M GOMEZ ALONSO S RUIZ PEREZ P | 2009 | Journal of Food Protection2009，72，4： | 1 |
| 5 | Prevalence of Mental Disorders in Europe: Results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) Project显示文摘 | Alonso J Angermeyer M C Bernert S | 2004 | Acta Psychiatry Scand Suppl2004，，420： | 1 |
| 6 | Preparation of MoS2 and WS2 catalysts by in situ decomposition of ammonium thiosalts显示文摘 | Alonso G Del Valle M Cruz J Petranovskii V LiceaClaverie A Fuentes S | | 0，，： | 1 |
| 7 | Oral immunization using tuber extracts from transgenic potato plants expressing rabbit haem orrhagic disease virus capsid protein显示文摘 | MARTIN-ALONOSO J M CASTANON S ALONSO P | 2003 | Transgenic Res2003，12，1： | 1 |
| 8 | Modeling the compres sive properties of glass fiber reinforced epoxy foam using the a nalysis of variance approaeh显示文摘 | ALONSO M V AUAD M L NUTT S | 2006 | Composites Science and Teeh nology2006，66，13： | 1 |
| 9 | Reactivity of highly cycled particles of CaO in a carbonation/calcination loop显示文摘 | Grasa G S Abanades J C Alonso M | 2008 | Chemical Engineering Journal2008，137，3： | 1 |
| 10 | Ziprasidone as coadjuvant treatment in resistant obsessive-compulsive disorder treatment 显示文摘 | IQLESIAS G C SANTAMARINA M S ALONSO VILLA M J | 2006 | Actas Exp Psiquiatr2006，34，4： | 1 |
| 11 | Microchemical Journal显示文摘 | Trujillo I S Alonso E V de Tortes A G Pavon J M C | 2012 | 101 : 872012，101，： | 1 |
| 12 | Membrane pilot reactorapplied to selective oxidation reactions 显示文摘 | Alonso M Lorences M J Patience G S | 2005 | Catalysis Today2005，104，234： | 1 |
| 13 | Glucomannan, a promising polysaccharide for biopharmaceutical purposes 显示文摘 | Alonso S M Teijeiro O D Remunan L C | 2009 | European Journal of Pharmaceutics and Biopharmaceutics2009，72，： | 1 |
| 14 | Regulation of ER–Golgi Intermediate Compartment Tubulation and Mobility by COPI Coats, Motor Proteins and Microtubules显示文摘 | MónicaTomás EmmaMartínez‐Alonso JoséBallesta José A.Martínez‐Menárguez | 2010 | Traffic2010，，5： | 1 |
| 15 | Isolation of clones of Isochrysis ga]bana rich in eicosapentaenoic acid 显示文摘 | Alonso D L Grima E M Perez J A S | 1992 | Aquculture1992，102，： | 1 |
| 16 | First insights into improvement of eicosapentaenoic acid content in Phaeodactylum tricornutum (Bacillariophyceae) by induced mutagenesis显示文摘 | Alonso D L Castillo C I S Grima E M | 1996 | J Phycol1996，32，： | 1 |
| 17 | Auxin response factors ARF6 and ARF8 promote jasmonic acid production and flower maturation 显示文摘 | Nagpal P Ellis C M Weber H Ploense S E Barkawi LS Guilfoyle T J Hagen G Alonso J M Cohen J D Farmer E E | 2005 | Development2005，132，： | 1 |
| 18 | A functional variant of lymphoid tyrosine phosphatase is associated with type Ⅰ diabetes显示文摘 | Bottini N Musumeci L Alonso A Rahmouni S Nika K Rostamkhani M | 2004 | Nat Genet2004，36，： | 1 |
| 19 | Percutaneous ureteral cathe- terization in laparoscopic surgery: value nephroscopy needle trocn' 显示文摘 | Alonso S Alvarez M Cabrera PM | 2010 | Urology2010，56，4： | 1 |
| 20 | Adaptive cleaning for RFID data steam显示文摘 | Jeffery S R Alonso G Franklin M J | 2006 | Technical Report UCB2006，14，2： | 1 |
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