Arachidyl amido cholanoic acid improves liver glucose and lipid homeostasis in nonalcoholic steatohepatitis
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
TOR Serine-Threonine Kinases
/ metabolism
Hemoglobin A1c
Methionine and choline deficient diet
Nonalcoholic fatty liver disease
Stearoyl-CoA desaturase 1
Steatohepatitis
Tricarboxylic acid cycle
Journal
World journal of gastroenterology
ISSN: 2219-2840
Titre abrégé: World J Gastroenterol
Pays: United States
ID NLM: 100883448
Informations de publication
Date de publication:
14 Sep 2020
14 Sep 2020
Historique:
received:
19
05
2020
revised:
19
06
2020
accepted:
13
08
2020
entrez:
28
9
2020
pubmed:
29
9
2020
medline:
15
5
2021
Statut:
ppublish
Résumé
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. 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. 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 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 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.
Sections du résumé
BACKGROUND
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
OBJECTIVE
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
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
RESULTS
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
CONCLUSION
CONCLUSIONS
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.
Identifiants
pubmed: 32982112
doi: 10.3748/wjg.v26.i34.5101
pmc: PMC7495035
doi:
Substances chimiques
Cholic Acids
0
Lipids
0
Methionine
AE28F7PNPL
MTOR protein, human
EC 2.7.1.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
AMP-Activated Protein Kinases
EC 2.7.11.31
Glucose
IY9XDZ35W2
aramchol
QE1Q24M65Y
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5101-5117Informations de copyright
©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict-of-interest statement: Dr. Mato is a Galmed Pharmaceuticals and OWL Metabolomics consultant and/or speaker. Dr. Hayardeny and Dr. Tzivirkun are Galmed Pharmaceuticals employees. Dr. Iruarrizaga-Lejarreta and Dr. Alonso are OWL Metabolomics employees. All other authors have nothing to disclose.
Références
Hepatol Commun. 2017 Nov;1(9):911-927
pubmed: 29159325
Hepatology. 2016 Jul;64(1):73-84
pubmed: 26707365
Hepatology. 2010 Jun;51(6):1972-8
pubmed: 20209604
J Physiol Biochem. 2016 Sep;72(3):485-94
pubmed: 27312217
Nat Rev Drug Discov. 2016 Nov 3;15(11):745-746
pubmed: 27807356
Cell. 2017 Mar 9;168(6):960-976
pubmed: 28283069
Oxid Med Cell Longev. 2018 Jun 11;2018:9547613
pubmed: 29991976
J Diabetes Sci Technol. 2017 May;11(3):611-617
pubmed: 27898388
Arch Med Res. 2010 Aug;41(6):397-404
pubmed: 21044742
Mol Cells. 2011 Dec;32(6):571-7
pubmed: 22083307
Cell Rep. 2018 Jun 12;23(11):3300-3311
pubmed: 29898400
Sci Rep. 2018 Apr 19;8(1):6289
pubmed: 29674640
Cell Mol Life Sci. 2019 Jan;76(1):99-128
pubmed: 30343320
Lipids Health Dis. 2016 Sep 17;15(1):159
pubmed: 27640119
Oncotarget. 2015 Feb 10;6(4):2509-23
pubmed: 25650664
Cell Metab. 2018 Feb 6;27(2):299-313
pubmed: 29153408
World J Hepatol. 2015 Jun 18;7(11):1450-9
pubmed: 26085906
Sci Rep. 2019 Nov 14;9(1):16810
pubmed: 31728041
Int J Mol Sci. 2013 Oct 15;14(10):20704-28
pubmed: 24132155
Biochim Biophys Acta Gene Regul Mech. 2019 Feb;1862(2):141-152
pubmed: 30605728
Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):251-62
pubmed: 22436748
Nat Protoc. 2016 Dec;11(12):2301-2319
pubmed: 27809316
Gastroenterology. 2017 May;152(6):1449-1461.e7
pubmed: 28132890
J Proteomics. 2015 Sep 8;127(Pt B):275-88
pubmed: 25668325
Prog Lipid Res. 2014 Jan;53:124-44
pubmed: 24362249
Clin Gastroenterol Hepatol. 2014 Dec;12(12):2085-91.e1
pubmed: 24815326
Science. 2011 Jun 24;332(6037):1519-23
pubmed: 21700865
Expert Rev Mol Diagn. 2016;16(3):343-55
pubmed: 26680319
Am J Gastroenterol. 2018 Nov;113(11):1649-1659
pubmed: 29880964
Lab Invest. 2010 Aug;90(8):1169-78
pubmed: 20368703
Nat Med. 2018 Jul;24(7):908-922
pubmed: 29967350
Clin Liver Dis. 2018 Feb;22(1):1-10
pubmed: 29128049