Inhibition, post-hydroxymethylglutaryl-CoA regulation and relation to cell growth of cholesterol biosynthesis in cultured human skin fibroblasts.
Cholesterol biosynthesis in cultured human skin fibroblasts was studied by [14C]acetic acid incorporation into non-saponifiable lipids and quantification of labeled cholesterol among its precursors. Synthesis was slow, in spite of a high 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA) activity and led to an accumulation of unexpected non-polar metabolites identified as C-30 sterones, but not C-27 sterol precursors. This supports a post-HMG-CoA regulation at the lanosterol demethylation step. Cholesterol biosynthesis was stimulated by cell culture in lipid depleted medium and was inhibited by pentadecane-2-one which acts mainly at two post-HMG-CoA steps: lanosterol demethylation and lathosterol isomerisation to cholesterol. A parallel pentadecane-2-one inhibition of cell growth was also observed, even when cells were cultured in the presence of whole serum. This indicates the existence of a relationship between endogenous cholesterol synthesis and cell growth and sheds additional light on the role of post-HMG-CoA regulation in this phenomenon.
D000085:Acetates / Q000378:metabolism; D019342:Acetic Acid; D000293:Adolescent; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002784:Cholesterol / Q000096:biosynthesis*; D004247:DNA / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000494:pharmacology; D012867:Skin / Q000166:cytology / Q000378:metabolism*
D000085:Acetates; D002250:Carbon Radioisotopes; D008077:Lipoproteins, LDL; D004247:DNA; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D019342:Acetic Acid