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Cell Rep. 2017 Jun 6;19(10):1997-2004. doi: 10.1016/j.celrep.2017.05.035.

Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans.

Author information

1
Department of Endocrinology and Metabolism, Academic Medical Center, 1105AZ Amsterdam, the Netherlands.
2
Department of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center, 1105AZ Amsterdam, the Netherlands.
3
Department of Radiology, Academic Medical Center, 1105AZ Amsterdam, the Netherlands.
4
Department of Endocrinology and Metabolism, Academic Medical Center, 1105AZ Amsterdam, the Netherlands; Department of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center, 1105AZ Amsterdam, the Netherlands; Metabolism and Reward Group, Netherlands Institute for Neuroscience, 1105BA Amsterdam, the Netherlands.
5
Department of Medicine, Academic Medical Center, 1105AZ Amsterdam, the Netherlands.
6
Department of Vascular Medicine, Academic Medical Center, 1105AZ Amsterdam, the Netherlands; Department of Internal Medicine, VU University Medical Center, 1081HV Amsterdam, the Netherlands; Institute for Cardiovascular Research, VU University Medical Center, 1081HV Amsterdam, the Netherlands.
7
Howard Hughes Medical Institute, Yale University, New Haven, CT 06519, USA.
8
Department of Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
9
Howard Hughes Medical Institute, Yale University, New Haven, CT 06519, USA; Department of Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA.
10
Department of Endocrinology and Metabolism, Academic Medical Center, 1105AZ Amsterdam, the Netherlands. Electronic address: m.j.serlie@amc.nl.

Abstract

Hepatic lipid accumulation has been implicated in the development of insulin resistance, but translational evidence in humans is limited. We investigated the relationship between liver fat and tissue-specific insulin sensitivity in 133 obese subjects. Although the presence of hepatic steatosis in obese subjects was associated with hepatic, adipose tissue, and peripheral insulin resistance, we found that intrahepatic triglycerides were not strictly sufficient or essential for hepatic insulin resistance. Thus, to examine the molecular mechanisms that link hepatic steatosis to hepatic insulin resistance, we comprehensively analyzed liver biopsies from a subset of 29 subjects. Here, hepatic cytosolic diacylglycerol content, but not hepatic ceramide content, was increased in subjects with hepatic insulin resistance. Moreover, cytosolic diacylglycerols were strongly associated with hepatic PKCε activation, as reflected by PKCε translocation to the plasma membrane. These results demonstrate the relevance of hepatic diacylglycerol-induced PKCε activation in the pathogenesis of NAFLD-associated hepatic insulin resistance in humans.

KEYWORDS:

NAFLD; diacylglycerol; glucose clamp; hepatic glucose production; hepatic steatosis; human; insulin resistance; obesity; protein kinase Cε

PMID:
28591572
PMCID:
PMC5469939
DOI:
10.1016/j.celrep.2017.05.035
[Indexed for MEDLINE]
Free PMC Article

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