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Nutritional Modulation of Guinea Pig Skin Hyperproliferation by Essential Fatty Acid Deficiency is Associated with Selective Down Regulation of Protein Kinase C-ß^1,2,

Departments of Dermatology and Nutrition, University of California, Davis, CA 95616

In a previous study we demonstrated that 13-hydroxyoctadecadienoic acid (13-HODE), a 15-lipoxygenase metabolite of linoleic acid is incorporated into epidermal phosphatidyl 4,5-bisphosphate (PtdIns 4,5-P₂) and released as 13-HODE-containing-diacylglycerol (13-HODE-DAG). In vitro, 13-HODE-DAG was shown to selectively inhibit epidermal total protein kinase C (PKC-ß) activity. To determine whether these observations are relevant in vivo, guinea pigs were made essential fatty acid deficient (EFAD) by feeding them a basal diet supplemented with 4% hydrogenated coconut oil for 8 wk. Tissue levels of putative 13-HODE-DAG, protein kinase C (PKC) isozymes and tissue hyperproliferation were determined in the epidermal preparations from skin of control safflower oil-fed guinea pigs, those fed EFAD diet and those fed EFAD diet followed by the control diet for 2 wk. Our data revealed that cutaneous 13-HODE and 13-HODE-DAG were significantly lower in EFAD animals than in safflower-fed controls. These reductions were associated with both elevated epidermal hyperproliferation and elevated expressions and activities of PKC- and ß-isozymes. Refeeding the animals with safflower oil for 2 wk replenished tissue levels of 13-HODE-DAG, which inversely correlated with the selective down regulation of PKC-ß expression and activity and the reversal of hyperproliferation. In contrast, although the expression and activity of PKC- was elevated in the epidermis of the EFAD guinea pigs, this elevated PKC- expression was not down regulated after refeeding the safflower oil diet to the animals. These results suggest that the epidermal level of 13-HODE plays a role in vivo in modulating cutaneous hyperproliferation via the generation of 13-HODE-DAG via signal transduction and its selective suppression of PKC-ß isozyme.

KEY WORDS: • linoleic acid • 13-hydroxyoctadecadienoic acid • 13-HODE-substituted diacylglycerol • protein kinase C-ß • guinea pigs

¹ Supported in part by Research Grant AM-30679 from the National Institutes of Health of the U.S. Public Health Service.

² The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with USC section 1734 solely to indicate this fact.

³ To whom correspondence should be addressed.

Manuscript received 1 July 1994. Revision accepted 6 July 1995.

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