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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 | Embolism using 16-slice multi-detector row CT: evaluation of different imaging reconstruction parameters显示文摘 | Heuschmid M Mann C Luz O | 2006 | J Comput Assist Tomogr2006，30，1： | 1 |
| 3 | Risk factors for osteoporosis and fractures in postmenopausal women between 50 and 65 years of age in a primary care setting in Spain : a questionnaire 显示文摘 | Luz Rentero M Carbonell C Casillas M | 2008 | Open Rheumatol J2008，2，1： | 1 |
| 4 | Distribution of polycyclic aromatic hydrocarbons in marine sediments and their potential toxic effects显示文摘 | Froehner S Maceno M Luz E C D | 2010 | Environmental Monitoring and Assessment2010，168，14： | 1 |
| 5 | Detection of pulmonary embolism using 16-slice muhidetector-row computed tomography: evaluation of different image reconstruction parameters 显示文摘 | HEUSCHMID M o MANN C LUZ O | 2006 | J Comput Assist Tomogr2006，30，1： | 1 |
| 6 | Flavonoids, flavonolignans and a phenylpropanoid from Onopordon corymbosum 显示文摘 | LUZ C M GARCIA B PEDRO J R | 1990 | Phytochemistry1990，9，2： | 1 |
| 7 | Comparativeoocyte morphology and fecundity of five characid species from S5o Francisco River basin, Brazil显示文摘 | Melo R M C Ferreira C M Luz R K | 2011 | J Appl Ichthyol2011，27，6： | 1 |
| 8 | Hot elastic modulus of Al2O3-Si C-Si O2-C castables显示文摘 | Luz A P Huger M Pandolfelli V C | 2011 | Ceramics International2011，37，7： | 1 |
| 9 | Struc-tural characterization of coagulant Moringa oera Lectin and its effect on hemostatic param- eters显示文摘 | Luz L A Silva M C Ferreira R S | 2013 | Int J Biol Macromol2013，58，： | 1 |
| 10 | A hybrid recommendation approach for a tourism system 显示文摘 | Lucas J P Luz N Moreno M N Anacleto R Figueiredo A A Martins C ( 2013 ) | 2013 | Expert Systems with Applications2013，40，9： | 1 |
| 11 | Hippocampal biomarkers of fear memory in an animal model of generalized anxiety disorder 显示文摘 | Dias G P Bevilaqua M C da Luz A C | 2014 | Behav Brain Res2014，15，263： | 1 |
| 12 | On the transport properties in granular or weakl, coupled superconductors显示文摘 | C A M dos Santos M S da Luz B Ferreira | 2003 | Physica C2003，391，： | 1 |
| 13 | The Influence of the DiluentSystem on the Porous Structure Formation of Copolymers Based on2-Vinylpyridine and Divinylbenzene 显示文摘 | Lima C T Luz F M Coutinho B | 2001 | Polymer2001，42，11： | 1 |
| 14 | Impact of moisture on in vitro germination of Metarhizium anisopliae and Beauveria bassiana and their activity on Triatoma infestans 显示文摘 | Lazzarini G M J Rocha L F N Luz C | 2006 | Mycological Research2006，110，： | 1 |
| 15 | Influence of morphology and surface charge on the suitability of palygorskite as drilling fluid 显示文摘 | Baltar C A M da Luz A B Baltar L M | 2009 | Applied Clay Science2009，42，： | 1 |
| 16 | Novel Gamma differential evolution approach for multiobjective transformer design optimization显示文摘 | Dos Santos Coelho L Mariani V C Da Luz M V F | 2013 | IEEE Transactions on Magnetics2013，49，5： | 1 |
| 17 | Impact of moisture on in vitro germination of Metarhiziurn anisopliae and Beauveria basciana and their activity on Triatoma infestans 显示文摘 | Lazzarini G M J Rocha L F N Luz C | 2006 | Mycological Research2006，11，4： | 1 |
| 18 | The influence of food restriction during different periods of pregnancy 显示文摘 | Griggio M A Luz J Gorgulho A A Sucasas C M | 1997 | Int J Food Sci Nutr1997，48，2： | 1 |
| 19 | Risk factors for osteopo- rosis and fractures in postmenopausal women between 50 and 65 years of age in a primary care setting in Spain: a questionnaire 显示文摘 | Luz Rentero M Carbonell C Casil- las M | 2008 | Open Rheumatol J2008，2，： | 1 |
| 20 | Controlling the cyto- toxicity of CdSe magic - sized quantum dots as a function of surface defect density 显示文摘 | SILVA A C A SILVA M J B LUZ F A C | 2014 | Nano Lett2014，14，： | 1 |
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