Nutritional Modulation of Guinea Pig Skin Hyperproliferation by Essential Fatty Acid Deficiency is Associated with Selective Down Regulation of Protein Kinase C-β

Abstract

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-β) 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-α and β-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-β expression and activity and the reversal of hyperproliferation. In contrast, although the expression and activity of PKC-α was elevated in the epidermis of the EFAD guinea pigs, this elevated PKC-α 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-β isozyme.