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Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis
Biddinger, Sudha B; Hernandez-Ono, Antonio; Rask-Madsen, Christian; Haas, Joel T; Aleman, Jose O; Suzuki, Ryo; Scapa, Erez F; Agarwal, Chhavi; Carey, Martin C; Stephanopoulos, Gregory; Cohen, David E; King, George L; Ginsberg, Henry N; Kahn, C Ronald
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.
PMCID:4251554
PMID: 18249172
ISSN: 1550-4131
CID: 2119022
Manipulation of Dietary Essential Amino Acids Prevents High-Fat Induced Non-Alcoholic Fatty Liver in Mice [Meeting Abstract]
Noguchi, Yasushi; Hara, Yoshiko; Shikata, Nahoko; Aleman, Jose O; Young, Jamey D; Yoshida, Shintaro; Mori, Masato; Kelleher, Joanne K; Takahashi, Michio; Stephanopoulos, Gregory
ISI:000208467804674
ISSN: 0892-6638
CID: 2119002
The p85alpha regulatory subunit of phosphoinositide 3-kinase potentiates c-Jun N-terminal kinase-mediated insulin resistance
Taniguchi, Cullen M; Aleman, Jose O; Ueki, Kohjiro; Luo, Ji; Asano, Tomoichiro; Kaneto, Hideaki; Stephanopoulos, Gregory; Cantley, Lewis C; Kahn, C Ronald
Insulin resistance is a defining feature of type 2 diabetes and the metabolic syndrome. While the molecular mechanisms of insulin resistance are multiple, recent evidence suggests that attenuation of insulin signaling by c-Jun N-terminal kinase (JNK) may be a central part of the pathobiology of insulin resistance. Here we demonstrate that the p85alpha regulatory subunit of phosphoinositide 3-kinase (PI3K), a key mediator of insulin's metabolic actions, is also required for the activation of JNK in states of insulin resistance, including high-fat diet-induced obesity and JNK1 overexpression. The requirement of the p85alpha regulatory subunit for JNK occurs independently of its role as a component of the PI3K heterodimer and occurs only in response to specific stimuli, namely, insulin and tunicamycin, a chemical that induces endoplasmic reticulum stress. We further show that insulin and p85 activate JNK by via cdc42 and MKK4. The activation of this cdc42/JNK pathway requires both an intact N terminus and functional SH2 domains within the C terminus of the p85alpha regulatory subunit. Thus, p85alpha plays a dual role in regulating insulin sensitivity and may mediate cross talk between the PI3K and stress kinase pathways.
PMCID:1899914
PMID: 17283057
ISSN: 0270-7306
CID: 2119012