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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 | Cardiovascular disease in women: a statement for healt hcare professionals from the American Heart Association 显示文摘 | Mosca L Manson J E Sut herland S E | 1997 | Circulation1997，96，： | 1 |
| 3 | Cardioprotective effects of stretch are mediated by activation of sarcolemmal, not mitochondrial, ATP- sensitive potassium channels 显示文摘 | Mosca S M | 2007 | Am J Physiol Heart Circ Physiol2007，293，2： | 1 |
| 4 | The socialcost of rheumatoid arthritis in Italy : the results of anestimation exercise 显示文摘 | TURCHETTI G BELLELLI S MOSCA M | 2014 | Reumatismo2014，65，6： | 1 |
| 5 | Talipes equinovarus and maternal smoking: a population-based case-control study in Washington state显示文摘 | SKELLY A C HOLT V L MOSCA V S etal | 2002 | J Teratol2002，66，2： | 1 |
| 6 | Squamous papilloma of the esophagus long term follow up显示文摘 | MOSCA S MANES G MONACOR et a l | 2001 | J Gastroenterol Hepatol2001，16，8： | 1 |
| 7 | Squamous papilloma of the esophagus:long-term follw-up显示文摘 | Mosca S Menes G Monaco R | | 0，，08： | 1 |
| 8 | Ischemic cardiovas- cular involvement in psoriasis : A systematic review 显示文摘 | Mosca S Gargiulo P Balato N | 2015 | Int J Cardiol2015，15，178： | 1 |
| 9 | Endoscopic management of foreignbodies in the gastrointestinal tract:report on a series of 414 adult patients显示文摘 | MOSCA S MANES G MARTINO R | 2001 | Endoscopy2001，33，8： | 1 |
| 10 | Which scope and which technique will enhance the success rate in ERCP for the Billroth Ⅱ patient显示文摘 | Mosca S | | 0，，02： | 1 |
| 11 | Endoscopic management of foreign bodies in the upper gastrointestinal tract:report on a series of 414adult patients显示文摘 | Mosca S Manes G Martino R | 2001 | Endoscopy2001，33，： | 1 |
| 12 | Therapy with pulse methylprednisolone and short course pulse cyclophosphamidie for diffuse proliferative glomorulonicphritis显示文摘 | Mosca M Neri R Giannessi S | 2001 | Lupus2001，10，4： | 1 |
| 13 | Multilineage potential of adult human mesenchymal stem cells 显示文摘 | Pittenger MF Mackay AM Beck SC Jaiswal RK Douglas R Mosca JD Moorman MA Simonetti DW Craig S Marshak DR | 1999 | Science1999，284，： | 1 |
| 14 | Late biliary tract complications after orthotopic liver transplantation:diagnostic and therapeutic role of endoscopic retrograde cholangiopancreatography显示文摘 | Mosca S Militerno G Guardascione M A | 2000 | J Gastroenterol Hepatol2000，15，： | 1 |
| 15 | Squamous Papillomaof the esophagus:long-term follow up显示文摘 | Mosca S Manes G Monaco R | 2001 | J GastroenterolHepatol2001，，18： | 1 |
| 16 | Silicon content of Italian mineral waters and its contribution to daily intake显示文摘 | Giammarioli S Mosca M Sanzini E | 2005 | J Food Sci2005，70，8： | 1 |
| 17 | Squamous papilloma of the esophagus: long-term follow up显示文摘 | Manes G Monaco R | 2001 | J Gastroenterol Hepatol2001，16，8： | 1 |
| 18 | Multi-model unfalsified adaptive switching supervisory control显示文摘 | BALDI S BATTISTELLI G MOSCA E TESI P | 2010 | Automatica2010，46，2： | 1 |
| 19 | Undifferentiated connective tissue diseases in 2004显示文摘 | Mosca M Baldini C Bombatdieri S | | 0，，： | 1 |
| 20 | Multiple model adaptive control with mixing: The discrete-time ease显示文摘 | BALDI S IOANNOU P MOSCA E | 2012 | IEEE Transactions on Automatic Control2012，57，4： | 1 |
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