title: Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis.
abstract: 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.
authors.affiliation: Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Sudha B
authors.initials: SB
authors.lastname: Biddinger
authors.forename: Antonio
authors.initials: A
authors.lastname: Hernandez-Ono
authors.forename: Christian
authors.initials: C
authors.lastname: Rask-Madsen
authors.forename: Joel T
authors.initials: JT
authors.lastname: Haas
authors.forename: José O
authors.initials: JO
authors.lastname: Alemán
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.forename: Erez F
authors.initials: EF
authors.lastname: Scapa
authors.forename: Chhavi
authors.initials: C
authors.lastname: Agarwal
authors.forename: Martin C
authors.initials: MC
authors.lastname: Carey
authors.forename: Gregory
authors.initials: G
authors.lastname: Stephanopoulos
authors.forename: David E
authors.initials: DE
authors.lastname: Cohen
authors.forename: George L
authors.initials: GL
authors.lastname: King
authors.forename: Henry N
authors.initials: HN
authors.lastname: Ginsberg
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology*; D004198:Disease Susceptibility; D050171:Dyslipidemias / Q000209:etiology*; D006937:Hypercholesterolemia / Q000209:etiology; D007333:Insulin Resistance; D008074:Lipoproteins / Q000097:blood; D008107:Liver Diseases; D051379:Mice; D018345:Mice, Knockout; D011972:Receptor, Insulin / Q000172:deficiency
chemical_list: D008074:Lipoproteins; D011972:Receptor, Insulin