Abstract | BACKGROUND: AIM: METHODS: Isolated primary mouse hepatocytes were incubated with 20 μmol/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 [P-ACCα/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 13C-uniformely 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 FA β-oxidation and oxidative phosphorylation.
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Authors | 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, José M Mato |
Journal | World journal of gastroenterology
(World J Gastroenterol)
Vol. 26
Issue 34
Pg. 5101-5117
(Sep 14 2020)
ISSN: 2219-2840 [Electronic] United States |
PMID | 32982112
(Publication Type: Journal Article)
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Copyright | ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved. |
Chemical References |
- Cholic Acids
- Lipids
- Methionine
- MTOR protein, human
- TOR Serine-Threonine Kinases
- AMP-Activated Protein Kinases
- Glucose
- aramchol
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Topics |
- AMP-Activated Protein Kinases
(metabolism)
- Animals
- Cholic Acids
- Disease Models, Animal
- Glucose
(metabolism)
- Homeostasis
- Humans
- Lipid Metabolism
- Lipids
- Liver
(metabolism)
- Male
- Methionine
- Mice
- Mice, Inbred C57BL
- Non-alcoholic Fatty Liver Disease
(drug therapy, metabolism)
- TOR Serine-Threonine Kinases
(metabolism)
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