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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 | Elevated insulin-like growth factor 1 receptor, hepatocyte growth factor receptor and telomerase protein expression in mild ulcerative colitis显示文摘 | Ferenc Sipos Orsolya Galamb László Herszényi Béla Molnár Norbert Solymosi Tamás Zágoni Lajos Berczi Zsolt Tulassay | 2008 | Scandinavian Journal of Gastroenterology2008，，3： | 2 |
| 3 | Characterization of the molecular mechanisms of quinolone resistance in Yersinia enterocolitica O: 3 clinical isolates 显示文摘 | Capilla S Ruiz J Goni P | 2004 | J Antimicrob Chemother2004，53，6： | 1 |
| 4 | Effect of temperature on the durability of class C fly ash belite cement in simulated radioactive liquid waste: Synergy of chloride and sulphate ions显示文摘 | Guerrero A Goni S Allegro V R | 2009 | J Hazardous Mater2009，165，13： | 1 |
| 5 | Corrosion hehaviour of steel in high alumina cement mortar sample: effect of chloride 显示文摘 | Goni S Andrade C Page C L | 1991 | Cement and Concrete Research1991，21，4： | 1 |
| 6 | Bilateral psoas abscess : atypical presentation of spinal tuberculosis 显示文摘 | Goni V Thapa BR Vyas S | 2012 | Archives of Iranian medi- cine2012，15，4： | 1 |
| 7 | Accelerated carbonation of Friedel's salt in calcium aluminate cement paste 显示文摘 | Goni S Guerrero A | 2003 | Cement and Concrete Research2003，33，： | 1 |
| 8 | Last glacial fire regime variability in western France inferred from microcharcoal pre- served in core MD04-2845, Bay of Biscay显示文摘 | Daniau A L Goni M F S Duprat J | 2009 | Quaternary Re- search2009，71，3： | 1 |
| 9 | Proteinases secretedby Fasciola hepatica degrade extracellular matrix and base-ment membrane components显示文摘 | Berasain P Goni F McGonigle S | 1997 | J Parasitol1997，83，： | 1 |
| 10 | Bilateral psoas abscess: atypical presentation of spinal tuberculosis 显示文摘 | GONI V THAPA B R VYAS S | 2012 | Arch Iran Med2012，15，4： | 1 |
| 11 | Accelerated carbonation of Friedel' s salt in calcium aluminate cement paste显示文摘 | Goni S Guerrero A | 2003 | Cement and Concrete Re- search2003，33，： | 1 |
| 12 | Coal blend combustion: Fusibility ranking from mineral matter composition 显示文摘 | Goni Ch Helle S Garcia X | 2003 | Fuel2003，82，1517： | 1 |
| 13 | Durability of class C fly ash belite cement in simulated sodium chloride radioactive liquid waste: Influence of temperature 显示文摘 | Guerrero A Goni S Allegro V R | 2009 | Journal of Hazardous Materials2009，162，： | 1 |
| 14 | The effect of Hurricane Liti on the distribution of organic matter in the inner Louisiana shelf (Gulf of Mexico, USA) 显示文摘 | Goni M A Gordon E S Monacci N M | 2006 | Continental Shelf Research2006，26，： | 1 |
| 15 | The effect of Hurricane Lili on the distribution of organic matter along the inner Louisiana shelf (Gulf of Mexico,USA)显示文摘 | GONI M A GORDON E S MONACCI N M | 2006 | Continental Shelf Research2006，26，： | 1 |
| 16 | Three-dimensional reconstruction of irregular foodstuffs 显示文摘 | Goni S M Purlis E Salvadori V O | 2007 | Journal of Food Engineering2007，82，4： | 1 |
| 17 | Geometric modelling of heterogeneous and complex foods显示文摘 | Goni S M Purlis E | 2010 | Journal of Food Engineering2010，97，4： | 1 |
| 18 | Limitations of KochSteinegger test to evaluate the durability of cement pastes in acid medium显示文摘 | Macías A Goni S Madri J | 1999 | Cement and Concrete Research1999，29，： | 1 |
| 19 | Bilateral psoas abscess: atypical presentation of spinal tuberculosis显示文摘 | Goni V Thapa BR Vyas S | 2012 | Arch Iran Med2012，15，4： | 1 |
| 20 | Accelerated calbollalion of Frieda's salt in calcium laminate cement paste显示文摘 | GONI S GUERRM'O A | 2003 | Cement and Concrete Re- search2003，，33： | 1 |
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