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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 | Variant angina associated with bitter orange in a dietary supplement显示文摘 | Gange C A Madias C Felix Gretzik E M | 2006 | Mayo Clinic Proc2006，81，： | 1 |
| 3 | Latent heat thermal energy storage using cylindrical capsule: Numerical and experimental investigations 显示文摘 | A Felix Regin S C Solanki J S Saini | 2006 | Renewable Energy2006，31，13： | 1 |
| 4 | Environmental impact and management of phosphogypsum 显示文摘 | Hanan T Mohamed C Felix A L | 2009 | Journal of Environmental Man- agement2009，90，8： | 1 |
| 5 | Preoperative assessment of deep myometrial and cervical invasion in endometrial carcinoma:comparison ofmagnetic resonance imaging and histopathologic evaluation显示文摘 | Vasconcelos C Felix A Cunha TM | 2007 | J Obstet Gynaecol2007，27，8： | 1 |
| 6 | Peripheral osteoma of the mandibular condyle显示文摘 | J C M A Mancini M Woltmann V B Felix | 2005 | Journal of the Chinese Medical Association2005，34，1： | 1 |
| 7 | Panhandle PCR:a technical advance to amplify MLL genomic translocation breakpoints显示文摘 | FELIX C A JONES D H | 1998 | Leukemia1998，12，6： | 1 |
| 8 | The effect of distance from light source on light intensity from curing lights 显示文摘 | Felix C A Price R B | 2003 | J Adhes Dent2003，5，4： | 1 |
| 9 | JOE : A mobile, inverted pendulum显示文摘 | Felix G Aldo D A Silvio C | 2002 | IEEE Transaction on Industrial Electronics2002，49，1： | 1 |
| 10 | JOE: A mobile inverted Pendulum 显示文摘 | Felix G Aldo D A Silvio C | 2002 | IEEE Transactions on Industrial Electronics2002，49，1： | 1 |
| 11 | Preoperative assessment of deep myometrial and cervical invasion in endometrial carcinoma: comparison of magnetic resonance imaging and histopathologic evaluation 显示文摘 | Vasconcelos C Felix A Cunha TM | 2007 | J Obstet Gynaecol2007，27，： | 1 |
| 12 | Solid-phase peptide synthesis of somatostatin using mild base cleavage of N alpha-9-fluorenylrnethyloxy- carbonyl amino acids显示文摘 | CHANG C D FELIX A M JIMENEZ M H | 1980 | Pept Protein Res1980，15，5： | 1 |
| 13 | Heat transfer characteristics of thermal energy storage system using PCM capsules: A review 显示文摘 | Felix Regin A Solanki S C Saini J S | 2007 | Renewable and Sustainable Energy Reviews2007，12，2008： | 1 |
| 14 | Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats显示文摘 | Simonides Warner S Mulcahey Michelle A Redout Everaldo M Muller Alice Zuidwijk Marian J Visser Theo J Wassen Frank W J S Crescenzi Alessandra da-Silva Wagner S Harney John Engel Felix B Obregon Maria-Jesús Larsen P Reed Bianco Antonio C Huan | 2008 | Journal of Clinical Investigation2008，，3： | 1 |
| 15 | Simultaneous determination of etoposide and its catechol metabolite in the plasma of pediatric patients by liquid chromatography / tandem mass spectrometry显示文摘 | PANG S K ZHENG N Y FELIX C A | 2001 | Journal of Mass Spectrometry2001，36，7： | 1 |
| 16 | Kernel-oriented algorithm for transmission expansion planning显示文摘 | Javier C Felix F Wu A | 2000 | IEEE Trans on Power Systems2000，15，4： | 1 |
| 17 | Gtdap-1 promotes autophagy and is required for planarian remodeling during regeneration and starvation显示文摘 | GONZALEZ-ESTEVEZ C FELIX D A ABOOBAKER A A | 2007 | Proc Natl Acad Sci USA2007，104，13： | 1 |
| 18 | Natural frequencies ofthin rectangular plates with holes or orthotropic patchescarrying an elastically mounted mass显示文摘 | Bambill D V Felix D H Rossit C A | 2006 | InternationalJournal of Solids and Structures2006，43，1415： | 1 |
| 19 | Field trip activity in anancient gold mine : Scientific literacy in informal education 显示文摘 | Lima A Vasconcelos C Felix N | 2010 | Public Understanding of Science2010，19，3： | 1 |
| 20 | Extracellular interaction of the voltage-dependent Ca2+ channel alpha2 delta and alphal subunits显示文摘 | Gurnett C A Felix R Campbell K P | | 0，，29： | 1 |
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