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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 | Growth of ZnO tetrapods for nanostructure-based gas sensors 显示文摘 | Calestani D Zha M Mosca R | 2010 | Sens Actuators B2010，144，2： | 1 |
| 3 | Closed versus open endotracheal suctioning in preterm infants:Effects on cerebral oxygenation and blood volume显示文摘 | Mosca FA Colnaghi M Lattanzio M | 1997 | Biol Neonate1997，72，1： | 1 |
| 4 | Absence of retroviral sequences in Graves' disease 显示文摘 | Humphrey M Mosca J Baker J | 1991 | Lancet1991，337，： | 1 |
| 5 | 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 |
| 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 | 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 |
| 8 | Phenotypic and function- al comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells显示文摘 | Majumdar M Thiede M Mosca J | 1998 | J Cell Physiol1998，176，1： | 1 |
| 9 | 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 |
| 10 | 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 |
| 11 | Pulmonary hypertension afteribuprofen prophylaxis in very preterm infants显示文摘 | Mosca F Bray M Stucchi I | 2002 | Lancet2002，360，： | 1 |
| 12 | Buried penis release in adults with suction lipectomy and abdominoplasty 显示文摘 | Adham M N Teimourian B Mosca P | 2000 | Plast Reconstr Surg2000，106，4： | 1 |
| 13 | An integrative ge- nomic approach reveals coordinated expression of intronic miR-335,miR-342,and miR-561 with deregulated host genes in multiple myeloma显示文摘 | Ronehetti D Lionetti M Mosca L | 2008 | BMC Med Genomics2008，1，： | 1 |
| 14 | 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 |
| 15 | Prevalence of thyroid dysfunctions in systemic lupus erythematosus 显示文摘 | Antonelli A Fallahi P Mosca M | 2010 | Metabolism2010，59，6： | 1 |
| 16 | Sleep duration,snoring habits,and cardiovascular disease risk factors in an ethnically diverse population显示文摘 | Mosca M Aggarwal B | 2012 | J Cardiovasc Nurs2012，27，3： | 1 |
| 17 | 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 |
| 18 | Hormone replaemamt therapy and cardiovascular disease : a statement for healthcare professicamls from the American Heart Association显示文摘 | MOSCA L COLLINS P HERRINGTON D M | 2001 | Circulation2001，104，： | 1 |
| 19 | Predictive teleoperation of constrained dynamic systems via Internet-like channels显示文摘 | Casavola A Mosca E Papini M | 2006 | IEEE Transactions on Control Systems Technology2006，14，4： | 1 |
| 20 | A randomized pilot trial comparing cyclosporine and azathioprine for maintenance therapy in diffuse lupus nephritis over four years显示文摘 | MORONI G DORIA A MOSCA M | 2006 | Clinical Journal of the American Society of Nephrology2006，1，5： | 1 |
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