Inhibition of Estrogen-Related Receptor α Blocks Liver Steatosis and Steatohepatitis and Attenuates Triglyceride Biosynthesis.
Journal
The American journal of pathology
ISSN: 1525-2191
Titre abrégé: Am J Pathol
Pays: United States
ID NLM: 0370502
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
29
10
2020
revised:
08
03
2021
accepted:
12
04
2021
pubmed:
25
4
2021
medline:
27
7
2021
entrez:
24
4
2021
Statut:
ppublish
Résumé
The estrogen-related receptor (ERR) family of orphan nuclear receptors are transcriptional activators for genes involved in mitochondrial bioenergetics and metabolism. The goal of this study was to explore the role of ERRα in lipid metabolism and the potential effect of inhibiting ERRα on the development of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). In the current study, three experimental mouse models: high-fat diet, high-carbohydrate diet, and a genetic model of hepatic insulin resistance where the liver hyperinsulinemia signal is mimicked via hepatic deletion of Pten (phosphatase and tensin homolog deleted on chromosome 10), the negative regulator of the insulin/phosphatidylinositol 3-kinase signaling pathway, were used. A recently developed small-molecule inhibitor for ERRα was used to demonstrate that inhibiting ERRα blocked NAFLD development induced by either high-carbohydrate diet or high-fat diet feeding. ERRα inhibition also diminished lipid accumulation and attenuated NASH development in the Pten null mice. Glycerolipid synthesis was discovered as an additional mechanism for ERRα-regulated NAFLD/NASH development and glycerophosphate acyltransferase 4 was identified as a novel transcriptional target of ERRα. In summary, these results establish ERRα as a major transcriptional regulator of lipid biosynthesis in addition to its characterized primary function as a regulator for mitochondrial function. This study recognizes ERRα as a potential target for NAFLD/NASH treatment and elucidates novel signaling pathways regulated by ERRα.
Identifiants
pubmed: 33894178
pii: S0002-9440(21)00162-0
doi: 10.1016/j.ajpath.2021.04.007
pmc: PMC8261472
pii:
doi:
Substances chimiques
Receptors, Estrogen
0
Triglycerides
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1240-1254Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK048522
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA154986
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK084241
Pays : United States
Organisme : NIAAA NIH HHS
ID : R24 AA012885
Pays : United States
Informations de copyright
Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Références
Biochem J. 2019 Jan 15;476(1):137-149
pubmed: 30552141
Cancer Res. 2009 Aug 1;69(15):6149-57
pubmed: 19622763
Mitochondrion. 2010 Aug;10(5):516-27
pubmed: 20561910
Hepatol Commun. 2017 Apr;1(2):153-167
pubmed: 29152604
Cell Metab. 2005 Jul;2(1):55-65
pubmed: 16054099
Genes Dev. 2010 Mar 15;24(6):537-42
pubmed: 20194433
Endocrinology. 2009 Oct;150(10):4463-72
pubmed: 19608650
Nature. 2010 Mar 4;464(7285):121-5
pubmed: 20203611
Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2082-7
pubmed: 14769918
Mol Biol Rep. 2012 Mar;39(3):3343-54
pubmed: 21732060
Mol Cell Biol. 2004 Oct;24(20):9079-91
pubmed: 15456881
Int J Mol Sci. 2019 Feb 22;20(4):
pubmed: 30813330
J Biol Chem. 2013 Aug 30;288(35):25007-25024
pubmed: 23836899
Hepatology. 2010 Feb;51(2):679-89
pubmed: 20041406
J Biol Chem. 2013 Sep 20;288(38):27299-27306
pubmed: 23908354
Int J Mol Sci. 2016 May 20;17(5):
pubmed: 27213358
Am J Pathol. 2010 May;176(5):2302-8
pubmed: 20348245
Hepatology. 2016 Jul;64(1):73-84
pubmed: 26707365
Biochem Biophys Res Commun. 2007 Jul 6;358(3):813-8
pubmed: 17512501
Mol Cell Biol. 2006 Apr;26(7):2772-81
pubmed: 16537919
Biochem J. 2020 Mar 13;477(5):1021-1031
pubmed: 32096546
Arthritis Rheum. 2011 Aug;63(8):2374-84
pubmed: 21506092
Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6472-7
pubmed: 15087503
J Biol Chem. 2003 Mar 14;278(11):9013-8
pubmed: 12522104
Genes Dev. 2007 Aug 1;21(15):1909-20
pubmed: 17671090
J Biol Chem. 1999 Aug 6;274(32):22618-26
pubmed: 10428842
J Biol Chem. 2009 Jan 23;284(4):2307-19
pubmed: 19036724
Cell. 2006 Aug 25;126(4):789-99
pubmed: 16923397
Endocrinology. 2018 May 1;159(5):2153-2164
pubmed: 29635284
J Lipid Res. 2006 Apr;47(4):745-54
pubmed: 16436371
J Clin Invest. 2001 Jun;107(11):1403-9
pubmed: 11390422
Cell Metab. 2007 May;5(5):345-56
pubmed: 17488637
Mol Cell Biol. 2003 Nov;23(22):7947-56
pubmed: 14585956
Mol Cancer Res. 2007 Jan;5(1):71-85
pubmed: 17259347
Nature. 1988 Jan 7;331(6151):91-4
pubmed: 3267207
Cell Metab. 2009 Nov;10(5):405-18
pubmed: 19883618
J Cell Biochem. 2006 Mar 1;97(4):673-83
pubmed: 16329141
Fibrogenesis Tissue Repair. 2016 Jun 14;9:8
pubmed: 27307790
Free Radic Res. 2013 Nov;47(11):854-68
pubmed: 23915028
Cell Metab. 2008 Feb;7(2):95-6
pubmed: 18249166
Trends Endocrinol Metab. 2008 Oct;19(8):269-76
pubmed: 18778951
Mol Cancer Ther. 2013 May;12(5):675-84
pubmed: 23443804
Arterioscler Thromb Vasc Biol. 2012 Feb;32(2):236-46
pubmed: 22155452
Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12378-83
pubmed: 14530391
Mol Cancer Res. 2011 Dec;9(12):1708-17
pubmed: 22009178
Oncogene. 2017 Oct 26;36(43):6020-6029
pubmed: 28671671
Gastroenterology. 2010 Dec;139(6):2170-82
pubmed: 20837017
J Clin Invest. 2004 Jun;113(12):1774-83
pubmed: 15199412
J Med Chem. 2011 Feb 10;54(3):788-808
pubmed: 21218783
Diabetologia. 2014 Dec;57(12):2576-85
pubmed: 25205222
Mol Endocrinol. 2008 Aug;22(8):1743-53
pubmed: 18258684
PLoS Genet. 2014 Dec 11;10(12):e1004789
pubmed: 25502566
J Biol Chem. 2011 Nov 4;286(44):38035-38042
pubmed: 21911493
Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Dec;1864(12):158521
pubmed: 31479733
Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18348-53
pubmed: 22042850
J Biol Chem. 2007 Jul 20;282(29):21005-14
pubmed: 17504763
Cell Metab. 2013 Apr 2;17(4):586-98
pubmed: 23562079
Eur J Nutr. 2014 Jun;53(4):1103-14
pubmed: 24197180
Mol Endocrinol. 2009 Jun;23(6):772-83
pubmed: 19264843
PLoS Genet. 2011 Jun;7(6):e1002143
pubmed: 21731503