Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis

Cell Metab. 2008 Feb;7(2):125-34. doi: 10.1016/j.cmet.2007.11.013.


Insulin resistance plays a central role in the development of the metabolic syndrome, but how it relates to cardiovascular disease remains controversial. Liver insulin receptor knockout (LIRKO) mice have pure hepatic insulin resistance. On a standard chow diet, LIRKO mice have a proatherogenic lipoprotein profile with reduced high-density lipoprotein (HDL) cholesterol and very low-density lipoprotein (VLDL) particles that are markedly enriched in cholesterol. This is due to increased secretion and decreased clearance of apolipoprotein B-containing lipoproteins, coupled with decreased triglyceride secretion secondary to increased expression of Pgc-1 beta (Ppargc-1b), which promotes VLDL secretion, but decreased expression of Srebp-1c (Srebf1), Srebp-2 (Srebf2), and their targets, the lipogenic enzymes and the LDL receptor. Within 12 weeks on an atherogenic diet, LIRKO mice show marked hypercholesterolemia, and 100% of LIRKO mice, but 0% of controls, develop severe atherosclerosis. Thus, insulin resistance at the level of the liver is sufficient to produce the dyslipidemia and increased risk of atherosclerosis associated with the metabolic syndrome.

Publication types

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

MeSH terms

  • Animals
  • Atherosclerosis / etiology*
  • Disease Susceptibility
  • Dyslipidemias / etiology*
  • Hypercholesterolemia / etiology
  • Insulin Resistance*
  • Lipoproteins / blood
  • Liver Diseases
  • Mice
  • Mice, Knockout
  • Receptor, Insulin / deficiency


  • Lipoproteins
  • Receptor, Insulin