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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 | Physiopathology of bacterial translocation and spontaneous bacterial peritonitis in cirrhosis显示文摘 | González Alonso R González García M Albillos Martínez A | 2007 | Gastroenterol Hepatol2007，30，2： | 1 |
| 4 | A reactivity study of chars obtained at different temperatures in relation to theirpetrographic characteristics 显示文摘 | Alonso M J G Borrego A G álvarez D | 2001 | Fuel Processing Technology2001，，69： | 1 |
| 5 | Development of phosphorylated glucomannan-coatod chitosan nanoparticles as nanocarriers for protein delivery显示文摘 | Cu(n)a M Alonso-Sandel M Remu(n)án-López C Pivel JP Alonso-Lebrero JL Alonso MJ | | 0，，9： | 1 |
| 6 | 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 |
| 7 | The African swine fever virus dynein-binding protein p54 induces infected cell apoptosis显示文摘 | Bruno Hernáez Gema D??az-Gil Mónica Garc??a-Gallo José Ignacio Quetglas Ignacio Rodr??guez-Crespo Linda Dixon José M Escribano Covadonga Alonso | 2004 | FEBS Letters2004，，1： | 1 |
| 8 | Transformer tank vibration modeling as a method of detecting winding deformations (Ⅰ):theoreticalfoundation显示文摘 | GARCíA B BURGOS J C ALONSO á M | 2006 | IEEE Transactions on Power Delivery2006，21，1： | 1 |
| 9 | Transformer tauk vibration modeling as a method of detecting winding deformations (H):experimental verification显示文摘 | GARCíA B BURGOS J C ALONSO á M | 2006 | IEEE Transactions on Power Delivery2006，21，1： | 1 |
| 10 | Occurrence of organochlorine insecticides,PCBs and PCB congeners in waters and sediments of the Ebro river(Spain)显示文摘 | Fernández M A Alonso C González M J | 1999 | Chemosphere1999，38，1： | 1 |
| 11 | Phthalates determination in physiological saline solutions by HPLC-ES-MS显示文摘 | Pérez Feás C Barciela Alonso M C Pe?a-Vázquez E | 2008 | Talanta2008，75，5： | 1 |
| 12 | Transformer tankvibration modeling as a method of detecting windingdeformations-Part I: Theoretical foundation显示文摘 | García B Burgos J C Alonso á M | 2006 | IEEETransactions on Power Delivery2006，21，1： | 1 |
| 13 | Direct LC-ES-MS/MS determination of phthalates in physiological saline solutions显示文摘 | Pérez Feás C Barciela Alonso M C Bermejo-Barrera P | 2011 | Journal of Chromatography B2011，879，34： | 1 |
| 14 | Xylooligosaccharides:manufacture and applications显示文摘 | Vázquez M J Alonso J L Domínguez H | 2000 | Trends in Food Science & Technology2000，11，11： | 1 |
| 15 | Transformer tankvibration modeling as a method of detecting windingdeformations-Part Ⅱ: Experimental verification 显示文摘 | García B Burgos J C Alonso á M | 2006 | IEEETransactions on Power Delivery2006，21，1： | 1 |
| 16 | Association of the Mediterranean dietary pattern with the incidence of depression:The Seguimiento Universidad de Navarra/University of Navarra follow-up(SUN)cohort显示文摘 | Sánchez-Villegas A Delgado-Rodríguez M Alonso A | 2009 | Arch Gen Psychiatry2009，66，10： | 1 |
| 17 | Tetraspanin-enriched microdomains:a functional unit in cell plasma membranes显示文摘 | Yáez Mó M Barreiro O Gordon Alonso M | 2009 | Trends Cell Biol2009，19，9： | 1 |
| 18 | Upper aerodigestive tract and lung tumors after liver transplantation显示文摘 | C Jiménez E Marqués C Loinaz D.R Romano R Gómez J.C Meneu G Hernández-Vallejo O Alonso M Abradelo I Garcia E Moreno | 2003 | Transplantation Proceedings2003，，5： | 1 |
| 19 | Isolation of green coffee chlorogenic acids using activated carbon显示文摘 | Suárez-Quiroz M L Alonso Campos A Valerio Alfaro G | 2014 | Journal of Food Composition and Analysis2014，33，1： | 1 |
| 20 | Lead isotope ratios in Spanish coals of different characteristics and origin显示文摘 | Díaz-Somoano M Suárez-Ruiz I Alonso J I G | 2007 | International Journal of Coal Geology2007，71，： | 1 |
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