Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis.
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.
Biddinger
Sudha B
SB
Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Hernandez-Ono
Antonio
A
Rask-Madsen
Christian
C
Haas
Joel T
JT
Alemán
José O
JO
Suzuki
Ryo
R
Scapa
Erez F
EF
Agarwal
Chhavi
C
Carey
Martin C
MC
Stephanopoulos
Gregory
G
Cohen
David E
DE
King
George L
GL
Ginsberg
Henry N
HN
Kahn
C Ronald
CR
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
D008074:Lipoproteins; D011972:Receptor, Insulin