Synthesis of ubiquinone and cholesterol in human fibroblasts: Regulation of a branched pathway

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86 Scopus citations

Abstract

The current studies demonstrate that cultured human flbroblasts utilize mevalonate for the synthesis of ubiquinone-10 as well as for the synthesis of cholesterol. Study of the regulation of this branched pathway was facilitated by incubating the cells with compactin (ML-236B), a competitive inhibitor of 3-hydroxy-3-methylglutaryI coenzyme A reductase, which blocked the formation of mevalonate within the cell. The addition of known amounts of [3H]mevalonate to the culture medium in the presence of compactin permitted the study of the relative rates of mevalonate incorporation into cholesterol and ubiquinone-10 under controlled conditions. When low concentrations of exogenous [3H]mevalonate (10 to 50 μm) were added to cells that were provided with exogenous cholesterol in the form of plasma low density lipoprotein (LDL), the cells incorporated the [3H]mevalonate into ubiquinone-10 at a rate that was two- to threefold faster than the incorporation into cholesterol. When the cells were deprived of exogenous LDL-cholesterol, the incorporation of [3H]mevalonate into ubiquinone-10 decreased and the incorporation of [3H]mevalonate into cholesterol increased. As a result, in the absence of exogenous cholesterol more than 60 times as much [3H]mevalonate was incorporated into cholesterol as into ubiquinone-10. Considered together with previous findings, the current data are compatible with a regulatory mechanism in which LDL inhibits cholesterol synthesis in fibroblasts at two points: (1) at the level of 3-hydroxy-3-methylglutaryl coenzyme A reductase, thereby inhibiting mevalonate synthesis, and (2) at one or more points distal to the last intermediate common to the cholesterol and ubiquinone-10 biosynthetic pathways. The latter inhibition allows ubiquinone-10 synthesis to continue in the presence of LDL despite a 98% reduction in mevalonate synthesis.

Original languageEnglish (US)
Pages (from-to)86-99
Number of pages14
JournalArchives of Biochemistry and Biophysics
Volume192
Issue number1
DOIs
StatePublished - Jan 1979

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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