Synthesis of long-chain polyunsaturated fatty acids is inhibited in vivo in hypercholesterolemic rabbits and in vitro by oxysterols.
Plasma total lipids, total cholesterol (cholesterol esters and free cholesterol) and oxysterol (mainly 7 beta-hydroxycholesterol (7 beta OH)) concentrations were significantly elevated in New Zealand rabbits fed a 2% cholesterol-containing diet with respect to controls fed the same diet without cholesterol. In addition, linoleic (18:2 n-6) and alpha-linolenic acid (18:3 n-3) plasma concentrations were significantly elevated in hypercholesterolemic rabbits, while concentrations of long-chain n-6 and n-3 derivatives were reduced. Studies in monocytic cell line THP-1 revealed that 7 beta OH markedly inhibited the conversion of 18:2 to 20:4 n-6 and of 18:3 to 22:6 n-3, indicating depression of the desaturation steps; in particular the inhibition was greater for the Delta 5 desaturation step. Furthermore, experiments of Real-Time PCR showed that 5-10 microM 7 beta OH decreased the Delta 5 gene expression. In conclusion, atherogenic oxysterols interfere with the production of long-chain polyunsaturated fatty acids from their precursors both in hypercholesterolemic rabbits and in cultured cells.
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Department of Pharmacological Sciences, University of Milan, via Balzaretti 9, 20133 Milan, Italy. patrizia.rise@unimi.it
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D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism; D002791:Cholesterol, Dietary; D004042:Dietary Fats, Unsaturated / Q000008:administration & dosage; D004195:Disease Models, Animal; D005231:Fatty Acids, Unsaturated / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000097:blood; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D008055:Lipids / Q000097:blood; D008297:Male; D009000:Monocytes / Q000187:drug effects; D011817:Rabbits
D002791:Cholesterol, Dietary; D004042:Dietary Fats, Unsaturated; D005231:Fatty Acids, Unsaturated; D006888:Hydroxycholesterols; D008055:Lipids; D002784:Cholesterol