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Diabetes. 2017 Aug;66(8):2241-2253. doi: 10.2337/db16-1147. Epub 2017 May 10.

Mechanisms of Insulin Resistance in Primary and Secondary Nonalcoholic Fatty Liver.

Author information

1
Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany.
2
German Center for Diabetes Research, München-Neuherberg, Germany.
3
Department of Molecular Cardiology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
4
Institute for Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany.
5
Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany.
6
Institute of Pathology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
7
Departments of Internal Medicine and Cellular & Molecular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT.
8
Department of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
9
Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany michael.roden@ddz.uni-duesseldorf.de.

Abstract

Nonalcoholic fatty liver disease is associated with hepatic insulin resistance and may result primarily from increased hepatic de novo lipogenesis (PRIM) or secondarily from adipose tissue lipolysis (SEC). We studied mice with hepatocyte- or adipocyte-specific SREBP-1c overexpression as models of PRIM and SEC. PRIM mice featured increased lipogenic gene expression in the liver and adipose tissue. Their selective, liver-specific insulin resistance was associated with increased C18:1-diacylglycerol content and protein kinase Cε translocation. SEC mice had decreased lipogenesis mediated by hepatic cholesterol responsive element-binding protein and featured portal/lobular inflammation along with total, whole-body insulin resistance. Hepatic mitochondrial respiration transiently increased and declined with aging along with higher muscle reactive oxygen species production. In conclusion, hepatic insulin resistance originates from lipotoxicity but not from lower mitochondrial capacity, which can even transiently adapt to increased peripheral lipolysis. Peripheral insulin resistance is prevented during increased hepatic lipogenesis only if adipose tissue lipid storage capacity is preserved.

PMID:
28490610
PMCID:
PMC5521856
DOI:
10.2337/db16-1147
[Indexed for MEDLINE]
Free PMC Article

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