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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 | Occurrence of Organochlorine Insecticides, PCBs and PCB Congeners in waters and Sediments of the Ebro River (Spain) 显示文摘 | Fernandez M A Alonso C Gonzalez M J | 1999 | Chemosphere1999，38，： | 2 |
| 3 | 3, 5-Bis (trifluoromethyl) phenyl sulfones in the modified julia olefination: application to the synthesis of resveratrol 显示文摘 | Alonso D A Najera C Varea M | 2004 | Tetrhaedron Lett2004，45，： | 1 |
| 4 | Is cisplatin-induced cell death always produced by apoptosis?显示文摘 | GONZALEZ V M FUERTES M A ALONSO C | 2001 | Mol Pharmaeol2001，59，4： | 1 |
| 5 | A moisture -in -oil model tor power transformer monitoring - part II: experimental verification 显示文摘 | GARCIA B BURGOS J C ALONSO A | 2005 | IEEE Transactions on Power Delivery2005，20，2： | 1 |
| 6 | Daily activity and intake rate patterns of wintering common cranes Grus grus 显示文摘 | Alonso L6pez J C Alonso L6pez J A | 1992 | Ardea1992，80，3： | 1 |
| 7 | Characterization of urinary tract symptoms and quality of life in patients with double pig tailed ureteral stents显示文摘 | Vega Vega A Garcia Alonso D Garcia Alonso C J | 2007 | Actas Urol Esp2007，31，7： | 1 |
| 8 | Nucleotide sequence of the genomic RNA of pepper mild mottle virus a resistance-breaking tobamovirus in pepper显示文摘 | ALONSO E GARCIA-LUQUE I DELA C A | 1991 | J Gen Virol1991，72，： | 1 |
| 9 | In vivo clot lysis of human thrombus with intravenous abciximab immunobubbles and Ultrasound显示文摘 | ALONSO A DEMPFLE C E DELLA-MARTINA A | 2009 | Thromb Res2009，124，1： | 1 |
| 10 | Hyperhomocysteinemia, low folate and vitamin B12 concentrations, and methylene tetrahydrofolate reductase mutation in cerebral venous thrombosis 显示文摘 | Cantu C Alonso E Jara A | 2004 | Stroke2004，35，8： | 1 |
| 11 | MR imaging findings in hepatic encephalopathy显示文摘 | Rovira A Alonso J Córdoba J | | 0，，09： | 1 |
| 12 | Real-time PCR designs to estimate nuclear and mitochondrial DNA copy number in fo- rensic and ancient DNA studies 显示文摘 | Alonso A Albarran C Garcia P | 2004 | Forensic Sei Int2004，139，23： | 1 |
| 13 | Family-based ter- ritoriality vs flocking in wintering common cranes Grus grus 显示文摘 | Alonso J C Bautista L M Alonso J A | 2004 | Journal of Avian Biology2004，35，5： | 1 |
| 14 | Enantioselective conjugate addition of ketones to β-nitrostyrenes catalyzed by 1, 2-amino alcohol-derived prolinamides 显示文摘 | ALMASI D ALONSO D A NAJERA C | 2006 | Tetrahedron: Asymmetry2006，17，14： | 1 |
| 15 | Inhibin A serum levels in proteinuric and nonproteinuric pregnancy-induced hypertension: Evidence for placental involvement in gestational hypertension显示文摘 | Casals E Gomez O Aibar C Cararach V Alonso PL Fortuny A | 2000 | Hypertens Preg2000，19，3： | 1 |
| 16 | Baseline of butyltin pollution in coastal sediments within the Basque Country (northern Spain), in 2007-2008显示文摘 | Rodriguez J G~ Solaun O Larreta J Segarra M J B Franco J Alonso J I G Sariego C Valencia V Borja A | 2010 | Marine Pollution Bulletin2010，60，1： | 1 |
| 17 | Integrated Buck- flyback converter as a high-power-factor off-line power supply 显示文摘 | ALONSO J M DALLA COSTA M A ORDIZ C | 2008 | IEEE Transactions on Industry Applications2008，55，3： | 1 |
| 18 | Screening of substrate analogs as potential enzyme inhibitors for the argi nine kinase of Trypanosoma cruzi显示文摘 | PEREIRA C A ALONSO G D IVAUDI S | 2003 | Journal of Eukaryotic Microbiology2003，50，2： | 1 |
| 19 | Influence of organic adsorbates on the under and overpotential deposition of copper on polycrystalline platinum electrodes 显示文摘 | Alonso C Pascual M J Abruna a H D | 1997 | Electrochimica Acta1997，42，11： | 1 |
| 20 | Amino acid changes within the Bunyamwera virus nucleocapsid protein differentially affect the mRNA transcription and RNA replication activities of assembled ribonucleoprotein templates显示文摘 | Walter C T Bento D F C Alonso A G Barr J N | 2011 | J Gen Virol2011，92，1： | 1 |
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