EFFECT OF DIETARY-FAT ON COLONIC PROTEIN-KINASE-C AND INDUCTION OF ABERRANT CRYPT FOCI

A major objective of the present study was to determine whether a high -fat diet affects early events during colon carcinogenesis. Female Spr ague-Dawley rats were injected with saline or azoxymethane (20 mg/kg) and fed either a normal (5% corn oil w/w) or a high (5% corn oil and 1 5% beef tallow w/w) fat diet. To assess the effect of a known tumor-pr omoting diet on the early events of neoplastic transformation, Study 1 examined the induction and growth of aberrant crypt foci (ACF) as wel l as of proliferative indices. The total number of ACF were similar in both groups even after 8 wk of dietary treatment; however, ACF with a ccelerated growth characteristics (greater than or equal to 4 crypts/f ocal lesion) were more prevalent (P less than or equal to 0.05) in the colons of animals fed the high-fat diet. Metaphase arrest cells and 5 '-bromo-2'-deoxyuridine labelled cells showed no appreciable response to dietary changes. To determine whether changes in colonic signal tra nsduction pathways represent an early response to dietary modification , Study 2 evaluated the activity of protein kinase C (PKC), proliferat ive indices and changes in phospholipid fatty acid profiles. In compar ison to the normal fat group, the colons of high-fat fed animals exhib ited higher (P less than or equal to 0.05) membranes and lower soluble PKC activity; however, proliferation patterns of these colons were no t altered. Changes in the membrane lipid composition were minor; howev er, an increase in the phosphatidylcholine/phosphatidylethanolamine ra tio and in 20:4n-6 was noted. Our results demonstrate that in comparis on to a normal-fat diet, a high-fat diet stimulated the growth of a po pulation of ACF, i.e., preneoplastic lesions leading to advanced growt h characteristics. In addition, a high-fat diet exerted a marked influ ence on total, cytosolic and membrane associated PKC activities. The f indings suggest that modulation of PKC may play a critical role at the early stages of colon carcinogenesis.