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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 | Drying kinetics of apple cylinders under combined hot air - microwave dehydration显示文摘 | ANDRES A BILBAO C FITO P | 2004 | Journal of Food Engineering2004，63，1： | 1 |
| 3 | Development and validation of an in Paeient satisfaction ques tionnaire显示文摘 | Gonzalez N Quintana JM Bilbao A | 2005 | Ine J Qual Health Cane2005，17，6： | 1 |
| 4 | p53 and Cyclin D1 as prognostic factors in squamous cell carcinoma of the larynx显示文摘 | VIEBA R BILBAO J ISPIZUA A | 2003 | Laryngoscope2003，113，： | 1 |
| 5 | Development and validation of an in-patient satisfaction questionnaire显示文摘 | González N Quintana J M Bilbao A | 2005 | Int J Qual Health Care2005，17，6： | 1 |
| 6 | Interaction between nitric oxide and urea under flow reactor condition显示文摘 | Alzueta M U Bilbao R Millera A | 1998 | Energy and Fuels1998，12，5： | 1 |
| 7 | Influence of the temperature and oxygen concentration on NOx reduction in the natural gas reburning process显示文摘 | BILBAO R MILLERA A ALZUETA M U | 1994 | Industrial Engineering Chemical Research1994，33，11： | 1 |
| 8 | Effect of patient char- acteristics on reported outcomes after total knee replacement 显示文摘 | Escobar A Quintana JM Bilbao A | 2007 | Rheumatology(Oxford)2007，46，1： | 1 |
| 9 | Drying kinetics of apple cylinders under combined hot air-microwave dehydration 显示文摘 | Andres A Bilbao C Fito P | 2004 | Journal of Food Engineering2004，63，1： | 1 |
| 10 | Drying kinetics of apple cylinders under combined hot air-microwave dehydration显示文摘 | ANDRES A BILBAO C FITO P | 2004 | Journal of Food Engineering2004，63，1： | 1 |
| 11 | Long-term effect of in vitro culture of mouse embryos with serum on mRNA expression of imprinting genes,development,and behavior显示文摘 | Fernández-Gonzalez R Moreira P Bilbao A | | 0，，： | 1 |
| 12 | Effect of nickel incorporation on the acidity and stability of HZSM-5 zeolite in the MTO process显示文摘 | Valle B Alonso A Atutxa A Gayubo A G Bilbao J | | 0，，1： | 1 |
| 13 | Evaluation of the use of different hydrocarbon fuels for gas reburning显示文摘 | MILLERA A ALZUETA M U PRADA L | 1997 | Fuel1997，76，1415： | 1 |
| 14 | Impact of new findings concerning urea thermal decomposition on the modeling of the urea-SNCR process显示文摘 | Alzueta M U Bilbao R Millera A | 2000 | Energy &Fuels2000，14，2： | 1 |
| 15 | The effect of temperature on the growth of strains of Kloeckera apiculata and Saccharomyces cerevisiae in apple juice fermentation显示文摘 | BILBAO A IRASTORZA A DUENAS M | 1997 | Lett Appl Microbiol1997，24，1： | 1 |
| 16 | Study of community acquired pneumonia: incidence, patterns of care, and outcomes in primary and hospital care显示文摘 | Capelastegui A Espana P Bilbao A | 2010 | J Infect2010，61，5： | 1 |
| 17 | Analysis of the mo- lecular parameters that could predict the risk of manifesting prema- ture ovarian failure in female premutation carriers of fragile X syn- drome显示文摘 | Tejada MI Garcfa - Alegrfa E Bilbao A | 2008 | Menopause2008，15，5： | 1 |
| 18 | Portal hypertension: diagnostic imaging and imaging -guided therapy显示文摘 | Bilbao JI Vivasl Delgado C Martinez Cuesta A | 2000 | Springer2000，11，： | 1 |
| 19 | Malignant trans formation of ganglioneuroma into spinal neuroblastoma in an adult: ease report显示文摘 | Kulkarni A V Bilbao J M Cusimano M D | 1998 | J Neurosurg1998，88，2： | 1 |
| 20 | Diffuse solar irradiation model evaluation in the north Mediterranean belt area 显示文摘 | de MIGUEL A BILBAO J AGUIAR R KAMBEZIDIS H NEGRD E | 2001 | Solar Energy2001，70，2： | 1 |
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