Summary
Inhibitors of hydroxymethylglutaryl coenzyme A reductase are used clinically to decrease blood levels of low-density lipoprotein cholesterol in hypercholesterolemic patients. However, little is known about the possible effects of these inhibitors on dolichol and cholesterol synthesis. Oral administration of mevinolin to rats was found here to decrease dolichol, dolichyl-P and coenzyme Q levels in the heart and skeletal muscle and to increase the hepatic dolichol level while decreasing the coenzyme Q content in this same organ. The amounts of dolichyl-P decreased in heart and muscle and increased in brain. Intraperitoneal administration also affected the levels of these lipids. The concentrations of blood lipids were not modified in the same manner as tissue lipids. Analysis of individual enzyme activities and of incorporation of [3H]acetate into various lipids of liver and brain slices demonstrated that both up- and down-regulation of different proteins occur in various tissues, resulting in modifications in lipid synthesis. Hypercholesterolemic patients were found to have high blood coenzyme Q levels, which are decreased upon pravastatin treatment, although they are still above control values. It appears that these HMG-coenzyme A reductase inhibitors do not selectively lower cholesterol levels, but that they also modify the dolichol and coenzyme Q content and synthesis both in the liver and various other tissues.
Similar content being viewed by others
Abbreviations
- CoA:
-
Coenzyme A
- CoQ:
-
coenzyme Q
- GGPP:
-
geranylgeranyl-PP
- GPP:
-
geranyl-PP
- FPP:
-
farnesyl-PP
- HDL:
-
high-density lipoprotein
- HMG:
-
hydroxymethylglutaryl
- LDL:
-
low-density lipoprotein
References
Alberts AW (1988) Discovery, biochemistry and biology of lovastatin. Am J Cardiol 62: 10J-15J
Edwards PA (1991) Regulation of sterol biosynthesis and isoprenylation of proteins.In: Vance DEA, Vance J (eds) Biochemistry of lipids, lipoproteins and membranes. Elsevier, Amsterdam, pp 383–401
Ekström TJ, Chojnacki T, Dallner G (1987) The α-saturation and terminal events in dolichol biosynthesis. J Biol Chem 262:4090–4097
Elmberger PG, Kalén A, Brunk U, Dallner G (1989) Discharge of newly-synthesized dolichol, dolichyl phosphate and ubiquinone with lipoproteins to rat liver perfusate and to the bile. Lipids 24:919–930
Elmberger PG, Kalén A, Lund E, Reihnér E, Eriksson M, Berglund L, Angelin B, Dallner G (1991) Effects of pravastatin and cholestyramine on products of the mevalonate pathway in familial hypercholesterolemia. J Lipid Res 32:935–940
Ericsson J, Appelkvist, EL, Thelin A, Chojnacki T, Dallner G (1992) Isoprenoid biosynthesis in rat liver peroxisomes —characterization of cis-prenyltransferase and squalene synthetase. J Biol Chem 267:18 707–18 714
Ericsson J, Runquist M, Thelin A, Andersson M, Chojnacki T, Dallner G (1993) Distribution of prenyltransferases in rat tissues — evidence for a cytosolic all-trans-geranylgeranyl diphosphate synthase. J Biol Chem 268:832–838
Ericsson J, Thelin A, Chojnacki T, Dallner G (1992) Substrate specificity of cis-prenyltransferase in rat liver microsomes. J Biol Chem 267:19730–19735
Goldstein JL, Brown MS (1990) Regulation of the mevalonate pathway. Nature 343:425–430
Löw P, Andersson M, Edlund C, Dallner G (1992) Effects of mevinolin treatment on tissue dolichol and ubiquinone levels in the rat. Biochim Biophys Acta 1128:253–259
MalteseWA (1990) Postranslational modification of proteins by isoprenoids in mammalian cells. FASEB J 4:3319–3328
Tollbom Ö, Valtersson C, Chojnacki T, Dallner G (1988) Esterification of dolichol in rat liver. J Biol Chem 262:1347–1352
Willis RAK, Folkers JL, Tucker CQ, Ye LJ, Xia, Tamagawa H (1990) Lovastatin decreases coenzyme Q levels in rats. Proc Natl Acad Sci USA 87:8928–8930
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Appelkvist, E.L., Edlund, C., Löw, P. et al. Effects of inhibitors of hydroxymethylglutaryl coenzyme A reductase on coenzyme Q and dolichol biosynthesis. Clin Investig 71 (Suppl 8), S97–S102 (1993). https://doi.org/10.1007/BF00226848
Issue Date:
DOI: https://doi.org/10.1007/BF00226848