Journal
CELL METABOLISM
Volume 7, Issue 2, Pages 125-134Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2007.11.013
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Funding
- NHLBI NIH HHS [HL55368, HL73030, R01 HL073030] Funding Source: Medline
- NIDDK NIH HHS [R37 DK031036, DK036588, R01 DK045935, R01 DK031036, R01 DK075850, DK053105, DK59637-01, R01 DK036588, R01 DK056626, R37 DK036588, DK45935, U24 DK059637, K12 DK063696, R01 DK048873, R01 DK053105, R01 DK073687, DK75850, DK073687, DK31036, P30 DK36836, R37 DK048873, P30 DK036836, K08DK073358] Funding Source: Medline
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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.
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