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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 | 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 |
| 4 | 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 |
| 5 | 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 |
| 6 | Sources and distribution of organic matter in a river-dominated estuary(Winyah Bay, SC, USA)显示文摘 | GONI M A TEIXEIRA M J PERKEY 13 W | 2003 | Estuarine Coastal and Shelf Science2003，57，56： | 1 |
| 7 | 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 |
| 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 | Sources and distribution of organic matter in a river dominated estuary (Winyah Bay, SC, USA) 显示文摘 | Goni M A Teixeira M J Perkey D W | 2003 | Estuarine Coastal and Shelf Science2003，57，： | 1 |
| 10 | 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 |
| 11 | 显示文摘 | Goni M A Eglinton T I | 1996 | Org Geochem1996，24，： | 1 |
| 12 | Sources and distribution of organic matter in a fiver-dominated estuary (Winyah Bay, SC, USA) 显示文摘 | GONI M A TEIXEIRA M J PERKEY D W | 2003 | Estuarine Coastal and Sheff Science2003，57，： | 1 |
| 13 | Distribution and sources of organic biomarkers in arctic sediments from the Mackenzie River and Beaufort Shelf显示文摘 | GONI M A YUNKER M B MACDONALD R W | 2000 | Marine Chemistry2000，71，12： | 1 |
| 14 | Heavy metal contamination in water,soil,and vegetables of the industrial areas in Dhaka,Bangladesh显示文摘 | AHMAD J U GONI M A | 2009 | Environmental Monitoring and Assessment2009，166，14： | 1 |
| 15 | 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 |
| 16 | Compartmentalization of ceramide signaling: physical foundations and biological effects 显示文摘 | KOLESNICK R N GONI F M ALONSO A | 2000 | J Cell Physiol2000，184，3： | 1 |
| 17 | A lipid molecular marker assess ment of sediments from the Northern Gulf of Mexico before and after the passage of Hurricane Lili 显示文摘 | Mead R Goni M A | 2006 | Organic Geochemistry2006，37，： | 1 |
| 18 | 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 |
| 19 | 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 |
| 20 | Effect of pressure on the refractive index of Ge and GaAs 显示文摘 | Goni A R Syassen K Cardon M | 1990 | Phys Rev B1990，41，10： | 1 |
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