The
insulin-like growth factors (IGFs) are mitogenic
polypeptides that have been linked to a variety of normal physiological processes as well as
neoplasia. Overexpression of several components of the IGF system is associated with hepatocarcinogenesis in humans and rodents. In rat liver, diets rich in n-6
polyunsaturated fatty acid (PUFA) enhance the development of preneoplastic lesions and
tumors. Therefore, the objective of this study was to determine the effect of these dietary
fatty acids on the hepatic expression of the various components of the IGF system. The
mRNA levels of
IGF-1 and the type 1 receptor were not different in livers of rats fed a diet containing 20%
corn oil (CO) compared with those fed 5% CO. Analysis of the
IGF binding proteins revealed that
insulin-like growth factor binding protein-1 (IGFBP-1) levels were altered by the amount and type of
dietary fat. A 2.5-fold induction of
IGFBP-1 mRNA occurred within 1 week after the animals were fed the 20%
corn oil diet compared with those fed 5% CO and was further enhanced to over 6-fold after 1 month. Furthermore,
IGFBP-1 protein was only detectable in the livers of animals fed the 20% CO diet. Induction of
IGFBP-1 mRNA (4.5-fold) also occurred in rats fed a high-fat diet containing safflower (rich in n-6 PUFAs) compared with those fed a high-fat diet containing
menhaden oil (rich in n-3 PUFAs). The induction of
IGFBP-1 mRNA was independent of serum
insulin levels and the development of
insulin resistance. Since
IGFBP-1 mRNA is upregulated in regenerating liver, we reasoned that the induction of
IGFBP-1 mRNA may be associated with an increase in cell proliferation; however, no difference was observed in the hepatic labeling index of rats fed the 20% CO compared with the 5% CO diet. In summary, these studies show a striking induction by dietary n-6 PUFAs of hepatic
IGFBP-1, a
protein that has been implicated in
liver cancer development.