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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 | Autophagy is an essential component of Drosophila immunity against vesicular stomatitis virus显示文摘 | Shelly S Lukinova N Bambina S | 2009 | Immunity2009，30，4： | 1 |
| 3 | Prolactin and autoimmunity显示文摘 | Shelly S Boaz M Orbach H | | 0，，6： | 1 |
| 4 | Incidence of Surgical Site Infection in the Foot and Ankle with Early Exposure and Showering of Surgical Sites : A Prospective Observation显示文摘 | Mindi F Paul D Shelly S | 1900 | The Journal of Foot and Ankle Surgery1900，53，2： | 1 |
| 5 | Fast Quantum Logic Gates with Trapped Ions Interacting with External Laser and Quantized Cavity Field Beyond the Lamb-Dick Regime显示文摘 | SHELLY SHARMA S VIDIELLA-BARRANCO A | 2003 | Phys Lett A2003，309，： | 1 |
| 6 | Na-pump 2-isoform specificallycouples to contractility in vascular smooth muscle:evidence fromgenetargeted neonatal mice显示文摘 | Shelly DA He S Moseley A | 2004 | Am J Physiol Cell Physiol2004，286，4： | 1 |
| 7 | Prospective multicenter study of the impact of the 21 - gene recurrence score assay on medical oncologist and patient adjuvant breast cancer treatment selection显示文摘 | Shelly S Lo Patricia B Mumby | 2010 | J Clin Onco12010，28，10： | 1 |
| 8 | The alpha(1)-and alpha(2)-isoforms of Na-K-ATPase play different roles in skeletal muscle contractility显示文摘 | Shelly DA Moseley AE James PF James JH Paul RJ | 2001 | Am J Physiol2001，281，3： | 1 |
| 9 | Autophagy is an essential component of Drosophila immunity against vesicular stomatitis virus显示文摘 | Shelly S Lukinova N Bambina S | 2009 | Immunity2009，30，4： | 1 |
| 10 | Auto- phagy is an essential component of Drosophila immunity against vesicular stomatitis virus 显示文摘 | SHELLY S LUKINOVA N BAMBINA S | 2009 | Immunity2009，30，4： | 1 |
| 11 | Introduction of a waterless alcohol-based hand rub in along-term-care facility显示文摘 | Lona M Shelly AM Rongjun S at al | 2003 | Infect Control Hosp Epidemiology2003，24，3： | 1 |
| 12 | Aspirin dose and six-month outcome after an acute coronary syndrome显示文摘 | Martin J Quinn Herbert D Aronow Robert M Califf Deepak L Bhatt Shelly Sapp Neal S Kleiman Robert A Harrington David F Kong David E Kandzari Eric J Topol | 2004 | Journal of the American College of Cardiology2004，，6： | 1 |
| 13 | Mismatch negativity: an index of a preattentive processing deficit in schizophrenia显示文摘 | Shelly A M Ward P B Catts S V | 1991 | Biol Psychiatry1991，30，： | 1 |
| 14 | Direct Microbial Reduction and Subsequent Preservation of Uranium in Natural Near-Surface Sediment显示文摘 | Yohey S Shelly D K Kenneth M K | 2005 | Applied and Environmental microbiology2005，71，4： | 1 |
| 15 | Spatial working memory deficits in autism显示文摘 | Shelly D S Nancy J Minshew N J | 2007 | J Autism Dev Disord2007，，37： | 1 |
| 16 | LKB1 /STRAD promotes axon initiation during neuronal polarization显示文摘 | Shelly M Cancedda L Heilshom S Sumbre G Poo M M | | 0，，03： | 1 |
| 17 | Local and long-range reciprocal regulation of cAMP and cGMP in axon/dendrite formation显示文摘 | Shelly M Lim B K Cancedda L Heilshom S C Gao H Poo M M | | 0，，5965： | 1 |
| 18 | Introduction of a water-less alcohol-based hand mb in a long-term-care facility显示文摘 | Lona M Shelly AM Rongjun S | 2003 | Infect Control Hosp Epidemiology2003，24，3： | 1 |
| 19 | Influence of male diet on male mating success and longevity and female remating in the mediterranean fruit fly (Diptera: Tephritidae)under laboratory conditions显示文摘 | Shelly T E Kennelly S | 2002 | Florida Entomologist2002，85，4： | 1 |
| 20 | Brain-derived neurotrophic factor is elevated in follicular fluid of women with PCOS显示文摘 | Johnstone EB Shelly WB Mellon S | 2008 | Fertil Steril2008，901，： | 1 |
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