In the corpulent James C. Russell corpulent (JCR:LA-cp) rat,
hyperinsulinemia leads to induction of lipogenic
enzymes via enhanced expression of
sterol-regulatory-
binding protein (SREBP)-1c. This results in increased hepatic
lipid production and
hypertriglyceridemia. Information regarding down-regulation of
SREBP-1c and lipogenic
enzymes by dietary
fatty acids in this model is limited. We therefore assessed de novo hepatic lipogenesis and hepatic and plasma
lipids in corpulent JCR rats fed diets enriched in
olive oil or
menhaden oil. Using microarray and Northern analysis, we determined the effect of these diets on expression of
mRNA for lipogenic
enzymes and other
proteins related to lipid metabolism. In corpulent JCR:LA-cp rats, both the
olive oil and
menhaden oil diets reduced expression of
SREBP-1c, with concomitant reductions in hepatic
triglyceride content, lipogenesis, and expression of
enzymes related to
lipid synthesis. Unexpectedly, expression of many peroxisomal proliferator-activated receptor-dependent
enzymes mediating
fatty acid oxidation was increased in livers of corpulent JCR rats. The
menhaden oil diet further increased expression of these
enzymes. Induction of
SREBP-1c by
insulin is dependent on
liver x receptor (LXR)alpha. Although hepatic expression of
mRNA for LXR itself was not increased in corpulent rats, expression of Cyp7a1, an LXR-responsive gene, was increased, suggesting increased LXR activity. Expression of
mRNA encoding
fatty acid translocase and
ATP-binding cassette subfamily DALD member 3 was also increased in livers of corpulent JCR rats, indicating a potential role for these
fatty acid transporters in the pathogenesis of disordered lipid metabolism in
obesity. This study clearly demonstrates that substitution of dietary
polyunsaturated fatty acid for
carbohydrate in the corpulent JCR:LA-cp rat reduces de novo lipogenesis, at least in part, by reducing hepatic expression of
SREBP-1c and that strategies directed toward reducing
SREBP-1c expression in the liver may mitigate the adverse effects of
hyperinsulinemia on hepatic
lipid production.