Epidermal HMG CoA reductase activity in essential fatty acid deficiency: barrier requirements rather than eicosanoid generation regulate cholesterol synthesis.
We showed previously that the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme of cholesterol biosynthesis, increases after both barrier disruption with organic solvents and in essential fatty acid deficiency (EFAD). Here, we treated EFAD hairless mice with linoleic acid, columbinic acid (C18: 3, n-6, trans; not metabolizable to known regulatory eicosanoids), prostaglandin E2 (PGE2), or latex occlusion, and determined transepidermal water loss (TEWL), epidermal protein content, and epidermal HMG CoA reductase activity. Increased TEWL rates in EFAD were accompanied by increased HMG CoA reductase activity (+130%, n = 6, p less than 0.01) and protein content (+69%; n = 6, p less than 0.025). Artificial restoration of the barrier by occlusion reduced the increase in enzyme activity and protein content toward normal, but barrier function, measured immediately after removal of the latex wrap, deteriorated further (TEWL: two-fold greater than EFAD unoccluded; p less than 0.01). Topical applications of either linoleate or columbinate (but not PGE2), normalized barrier function, HMG CoA reductase activity, and protein content. These results show that a) barrier function modulates HMG CoA reductase activity; b) reduction of cholesterol synthesis with occlusion results in a further deterioration in barrier function, suggesting that increased synthesis is a protective homeostatic response; and c) the barrier abnormality reflects a requirement for specific fatty acids for the barrier rather than resulting from epidermal hyperplasia or decreased prostaglandin generation.
Proksch
E
E
Department of Dermatology, University of Kiel, Germany.
Feingold
K R
KR
Elias
P M
PM
D000818:Animals; D002463:Cell Membrane Permeability / Q000502:physiology; D002784:Cholesterol / Q000096:biosynthesis; D015777:Eicosanoids / Q000378:metabolism; D004817:Epidermis / Q000201:enzymology; D005228:Fatty Acids, Essential / Q000172:deficiency*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D006965:Hyperplasia / Q000201:enzymology; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D012867:Skin / Q000201:enzymology* / Q000473:pathology
D015777:Eicosanoids; D005228:Fatty Acids, Essential; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases