Mechanisms of Insulin Resistance in Primary and Secondary Nonalcoholic Fatty Liver

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Animals
  • Diglycerides / metabolism
  • Female
  • Hepatocytes / metabolism
  • Insulin Resistance / physiology*
  • Lipogenesis / genetics*
  • Lipolysis / genetics
  • Liver / cytology
  • Liver / physiopathology
  • Mice
  • Mice, Transgenic
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / physiopathology*
  • Protein Kinase C-epsilon / metabolism
  • Protein Transport
  • Reactive Oxygen Species / metabolism
  • Sterol Regulatory Element Binding Protein 1 / metabolism*

Substances

  • Diglycerides
  • Reactive Oxygen Species
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Protein Kinase C-epsilon