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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 | Record of terrestrial organic matter composition in Amazon fan sediments显示文摘 | GONI M A | 1997 | Proceedings of the Ocean Drilling Program Scientific Resuhs1997，155，51： | 1 |
| 3 | Ocean thermal structure monitoring could aid in the intensity forecast of tropical cyclones 显示文摘 | Goni G J Trinanes J A | 2003 | Eos Trans Amer Geo- phys Union2003，84，： | 1 |
| 4 | A reassessment of the sources and importance of land derived organic matter in sur face sediments from the Gulf of Mexico显示文摘 | GONI M A RUTTENBERG K C EGLINTON T I | 1998 | Geochimica et Cosmochimica Acta1998，62，18： | 1 |
| 5 | New freeze-drying method for synthesis 显示文摘 | Palomares V Goni A Muro I G | 2007 | J Power Sources2007，171，： | 1 |
| 6 | Effect of dietary grape pomace and vitamin E on growth performance,nutrient digestibility,and susceptibility to meat lipid oxidation in chickens显示文摘 | Goni I Brenes A Centeno C | 2007 | Pouh Sci2007，86，： | 1 |
| 7 | 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 |
| 8 | Palmitoylcarnitine, a surface- active metabolite显示文摘 | Goni FM Requero MA Alonso A | 1996 | FEBS Lett1996，390，1： | 1 |
| 9 | In vitro determination of the indigestible fraction in foods : An alternative to dietary fiber analysis显示文摘 | Saura- Calixto F Garcia- Alonso A Goni I | 2006 | Journal of Agricultural Food Chemistry2006，48，： | 1 |
| 10 | 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 |
| 11 | Modeling gene sequences over time in 2009 H1N1 Influenza A virus populations显示文摘 | Goni N Fajardo A Moratorio G | 2009 | J Virol2009，6，： | 1 |
| 12 | 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 |
| 13 | Relationship between Physical Education Class and the Enhancement of Fifth Grade Pupils' Selfconcept显示文摘 | GONI A ZULAIKA L | 2000 | Perceptual Motor Skills2000，91，24： | 1 |
| 14 | 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 |
| 15 | Biophysical properties of sphingosine,ceramidesand other simple sphingolipids 显示文摘 | Goni FM Sot J Alonso A | 2014 | Biochem Soc Trans2014，42，5： | 1 |
| 16 | Accumulation of volatile compounds during ageing of two red wines with different composition 显示文摘 | Cerdan T G Goni D T Azpili A | 2004 | Journal of Food Engineering2004，65，： | 1 |
| 17 | A reassessment of the sources and importance of land-derived organic matter in surface sediments from the Gulf of Mexico 显示文摘 | GONI M A RUTTENBERG K C EGLINTON T I | 1998 | Geochimica et Cosmochimica Acta1998，62，18： | 1 |
| 18 | Mutation in the gyrA gene of quinolone-resistant clinical isolates of Acinetobacter baumannii 显示文摘 | Vila J Ruiz J Goni P Marcos A | 1995 | Antimicrob Agents Chemother1995，39，5： | 1 |
| 19 | 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 |
| 20 | Fruit load and can-opy shading affect leaf characteristics and net gas ex-change of Spring'navel orange trees显示文摘 | Syvertsen J P Goni C Otero T A | | Tree Physi-ology0，，： | 1 |
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