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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Insulin-resistant apoB/BATless mice have hypertriglyceridemia because of increased assembly and secretion of very low density apolipoprotein B (apoB) and triglycerides compared with mice expressing only apoB (Siri, P., Candela, N., Ko, C., Zhang, Y., Eusufzai, S., Ginsberg, H. N., and Huang, L. S. (2001) J. Biol. Chem. 276, 46064 -46072). Despite increased very low density lipoprotein secretion, apoB/BATless mice have fatty livers. We found that hepatic mRNA levels of key lipogenic enzymes, acetyl-CoA carboxylase, fatty-acid synthase, and stearoyl-CoA desaturase-1 were increased in apoB/BATless mice compared with levels in apoB mice, suggesting increased lipogenesis in apoB/BATless mice. This was confirmed by determining incorporation of tritiated water into fatty acids. Neither the hepatic mRNA of the lipogenic transcription factor, SREBP-1c (sterol-response element-binding protein 1c), nor the nuclear levels of the mature form of SREBP-1 protein were elevated in apoB/BATless mice. By contrast, hepatic levels of peroxisomal proliferator-activated receptor 2 (PPAR␥2) mRNA and protein were specifically increased in apoB/BATless mice, as were hepatic mRNA levels of two targets of PPAR␥, CD36 and aP2. Treatment of apoB/BATless mice for 4 weeks with intraperitoneal injections of a PPAR␥ antisense oligonucleotide resulted in dramatic reductions of both PPAR␥1 and PPAR␥2 mRNA, PPAR␥2 protein, and mRNA levels of fatty-acid synthase and acetyl-CoA carboxylase. These changes were associated with decreased hepatic de novo lipogenesis and hepatic triglyceride concentrations. We conclude that hepatic steatosis in apoB/ BATless mice is associated with elevated rates of hepatic lipogenesis that are linked directly to increased hepatic expression of PPAR␥2. The mechanism whereby hepatic Ppar␥2 gene expression is increased and how PPAR␥2 stimulates lipogenesis is under investigation.We reported previously that apoB/BATless mice, a model generated by crossing mice expressing human apolipoprotein B (apoB) 3 (1) with mice lacking brown adipose tissue (BATless) (2), have hypertriglyceridemia and hypercholesterolemia because of a 2-3-fold increase in the secretion of very low density lipoprotein (VLDL) apoB and triglycerides (TG) relative to mice expressing apoB only (3). Similar levels of apoB mRNA in the livers of apoB and apoB/BATless mice indicated that the differences in apoB secretion resulted from differences in posttranscriptional regulation of VLDL assembly and secretion (4). There were no differences in hepatic levels of microsomal triglyceride transfer protein mRNA (3), a critical factor in the early co-and post-translational regulation of apoB-containing lipoprotein secretion (5). Low density lipoprotein receptor mRNA levels in liver were higher in apoB/BATless compared with apoB mice (3), indicating that increased apoB secretion in apoB/BATless mice did not result from reduced interactions of the low density lipoprotein receptor with nascent apoB lipoproteins (6).Associated with a rising prevalence of obesity and insuli...