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J Biol Chem. 2019 Feb 8;294(6):2009-2020. doi: 10.1074/jbc.RA118.005184. Epub 2018 Dec 6.

Thioesterase superfamily member 2 promotes hepatic insulin resistance in the setting of glycerol-3-phosphate acyltransferase 1-induced steatosis.

Author information

1
From the Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York 10021.
2
the Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institute, 14152 Huddinge, Sweden.
3
the Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan, and.
4
the Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina 27599.
5
From the Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York 10021, dcohen@med.cornell.edu.

Abstract

Hepatic insulin resistance in the setting of steatosis is attributable at least in part to the accumulation of bioactive lipids that suppress insulin signaling. The mitochondria-associated glycerol-3-phosphate acyltransferase 1 (GPAT1) catalyzes the first committed step in glycerolipid synthesis, and its activity diverts fatty acids from mitochondrial β-oxidation. GPAT1 overexpression in mouse liver leads to hepatic steatosis even in the absence of overnutrition. The mice develop insulin resistance owing to the generation of saturated diacylglycerol and phosphatidic acid molecular species that reduce insulin signaling by activating PKCϵ and by suppressing mTORC2, respectively. Them2, a mitochondria-associated acyl-CoA thioesterase, also participates in the trafficking of fatty acids into oxidative versus glycerolipid biosynthetic pathways. Them2 -/- mice are protected against diet-induced hepatic steatosis and insulin resistance. To determine whether Them2 contributes to hepatic insulin resistance due to hepatic overexpression of GPAT1, recombinant adenovirus was used to overexpress GPAT1 in livers of chow-fed Them2 +/+ and Them2 -/- mice. Hepatic GPAT1 overexpression led to steatosis in both genotypes. In the setting of GPAT1 overexpression, glucose tolerance was reduced in Them2 +/+ but not Them2 -/- mice, without influencing whole-body insulin sensitivity or basal hepatic glucose production. Improved glucose tolerance in Them2 -/- mice was associated with reduced PKCϵ translocation. Preserved insulin receptor activity was supported by Thr-308 phosphorylation of Akt following GPAT1 overexpression in Them2 -/- hepatocytes. These findings suggest a pathogenic role of Them2 in the biosynthesis of glycerolipid metabolites that promote hepatic insulin resistance.

KEYWORDS:

diacylglycerol; fatty acid; fatty acid metabolism; insulin resistance; liver; triacylglycerol

PMID:
30523156
PMCID:
PMC6369296
[Available on 2020-02-08]
DOI:
10.1074/jbc.RA118.005184
[Indexed for MEDLINE]

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