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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 | Effects of the somatostatin analog Lanreotide on the circulating level of chromogranin - A, prostate - specific antigen, and insulin like growth factor - 1 in advanced prostate cancer patients 显示文摘 | Berruti A Dogliotti L Mosca A | 2001 | Prostate2001，47，3： | 1 |
| 3 | High dose, extended-in- terval colistin administration in critically ill patients: is this the right dosing strategy? a preliminary study 显示文摘 | Dalfino L Puntillo F Mosca A | 2012 | Clin Infect Dis2012，54，12： | 1 |
| 4 | Structured zeolite NaX coatings on ceramic cordierite monolith supports for PSA applications显示文摘 | Alessandra Mosca Jonas Hedlund Paul A Webley | 2010 | Microp Mesop Mater2010，130，： | 1 |
| 5 | Circulating neuroendocrine markers in patients with prostate carcinoma显示文摘 | Berruti A Dogliotti L Mosca A | 2000 | Cancer2000，88，11： | 1 |
| 6 | Control under Constraints:An Application of the Command Governor Approach to an Inverted Pendulum显示文摘 | Casavola A Mosca E Papini M | 2004 | IEEE Trans on Control Systems Technology2004，12，1： | 1 |
| 7 | Comparison of corneal aberration changes after laser in situ keratomileusis performed with mechanical microkeratome and IntraLase femtosecond laser:1-year follow-up显示文摘 | Buzzonetti L Petrocelli G Valente P Tamburrelli C Mosca L Laborante A | | 0，，2： | 1 |
| 8 | The plant amino acid mimosine may inhibit initiation at origins of replication in Chinese hamster cells显示文摘 | Mosca P J Dijkwel P A Hamlin J L | 1992 | Mol Cell Biol1992，12，10： | 1 |
| 9 | 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 |
| 10 | Implementation of a quantum search algorithm on a quantum computer显示文摘 | Jones J A Mosca M Hansen R H | 1998 | Nature1998，393，： | 1 |
| 11 | HbAlc stan- dardisation : history, science and politics 显示文摘 | John WG Mosca A Weykamp C | 2007 | Clin Biochem Rev2007，28，4： | 1 |
| 12 | Oscillatory interlayer exchange and magnetoresistance in Fe/Cu multilayers显示文摘 | PETROFF F BARTH(E)LEMY A MOSCA D H | 1991 | Phys Rev B1991，44，10： | 1 |
| 13 | Independent prognostic role of circulating chromogranin A in prostate cancer patients with hormone-refractary disease 显示文摘 | Berruti A Mosca A Tucci M | 2005 | Endocr Relat Cancer2005，12，1： | 1 |
| 14 | High-dose, extended-in- terval calistin administration in critically ill patients: is this the right dosing strategy? A preliminary study 显示文摘 | Dalfino L Puntillo F Mosca A | 2012 | Clin Infect Dis2012，54，12： | 1 |
| 15 | Chromogranin A expression in patients with hormone naive prostate cancer predicts the development of hormone refractory disease 显示文摘 | Berruti A Mosca A Porpiglia F | 2007 | J Urol2007，178，3： | 1 |
| 16 | Molecular and cellular signa- tures of human vaccine adjuvants 显示文摘 | Mosca F Tritto E Muzzi A | 2008 | Proc Natl Acad Sci USA2008，105，10： | 1 |
| 17 | A randomized pilot trial compa- ring cyclosporine and azathioprine for maintenance therapy in dif- fuse lupus nephritis over four years 显示文摘 | Moroni G Doria A Mosca M | 2006 | Clin J Am Soc Nephrol2006，1，5： | 1 |
| 18 | Prevalence of thyroid dysfunctions in systemic lupus erythematosus 显示文摘 | Antonelli A Fallahi P Mosca M | 2010 | Metabolism2010，59，6： | 1 |
| 19 | State of the art review : techniques to avoid pin loosening and infection in external fixation显示文摘 | Moroni A Vannini F Mosca M | 2002 | Orthop Trau- ma2002，16，3： | 1 |
| 20 | 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 |
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