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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 | 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 |
| 3 | 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 |
| 4 | 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 |
| 5 | Gelatinization and retrogradation of native starch from cherimoya fruit during ripening, using differential scanning calorimetry显示文摘 | GONI O ESCREBANO M I MERODIO C | 2008 | LWT2008，41，2： | 1 |
| 6 | Antimicrobial activity in the vapour phase of a combination of cinnamon and clove essential oils显示文摘 | Goni P Lopez P Sdnchez C | 2009 | Food Chemistry2009，116，4： | 1 |
| 7 | Antinucrobial activity in the vapour phase of a combination of cinnamon and clove essential oils显示文摘 | Goni P L6pez P S6nchz C | 2009 | Food Chemistry2009，116，： | 1 |
| 8 | 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 |
| 9 | 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 |
| 10 | 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 |
| 11 | Antimicrobial activity in the vapour phase of a combination of cinnamon and clove essential oils显示文摘 | Goni P Lopez P Sanchez C | 2009 | Food Chemistry2009，116，4： | 1 |
| 12 | Systematic study of stacking fault energies of random Al-based alloys 显示文摘 | SCHUHESS T C TURCHI P E A GONIS A NIEH T G | 1998 | Acta Materialia1998，46，6： | 1 |
| 13 | Antimicrobial activity in the vapour phase of a combination of cinnamon and clove essential oils显示文摘 | GONI P LOPEZ P SANCHEZ C | 2009 | Food Chemistry2009，116，： | 1 |
| 14 | 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 |
| 15 | Sources and contribution of terrigenous organic carbon to surface sediments in the Gulf of Mexico显示文摘 | Goni M A Ruttenberg K C Eglinton T I | | 0，，： | 1 |
| 16 | Phosphorus distribution,C : N : P ratios,and δ^13 Coc in arctic, temperate, and tropical coastal sediments:Tools for characterizing bulk sedimentary organic matter显示文摘 | Ruttenberg K C Goni M A | 1997 | Marine Geology1997，139，： | 1 |
| 17 | Coal Blend Combustion Fusibility Rank from Mineral Matter Composition显示文摘 | Goni C Helle S Gareia X | 2003 | Fuel2003，82，： | 1 |
| 18 | Polymorphism of diflunisal: isolation and solid-state characteristics of a new crystal form显示文摘 | Martinez-Oharriz M C Martin C Goni M M Rodriguez- Espinosa C lIarduya-Apaolaza D Tros M C Sanchez M | 1994 | Journal of Pharmaceutical Sciences1994，83，2： | 1 |
| 19 | Phosphorus distribution, C:N:P ratios, and δ13Coc in arctic, temperate, and tropical coastal sediments: tools for characterizing bulk sedimentary organic matter显示文摘 | Ruttenberg K C Goni M A | 1997 | Marine Geology1997，139，： | 1 |
| 20 | Source and contribution of terrigenous organic carbon on surface sediments in the Gulf of Mexico显示文摘 | Goni M A Ruttenberg K C Eglinton T I | 1997 | Nature1997，389，： | 1 |
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