TY - JOUR
T1 - Synthesis of ubiquinone and cholesterol in human fibroblasts
T2 - Regulation of a branched pathway
AU - Faust, Jerry R.
AU - Goldstein, Joseph L.
AU - Brown, Michael S.
PY - 1979/1
Y1 - 1979/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0018369386&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0018369386&partnerID=8YFLogxK
U2 - 10.1016/0003-9861(79)90074-2
DO - 10.1016/0003-9861(79)90074-2
M3 - Article
C2 - 219777
AN - SCOPUS:0018369386
SN - 0003-9861
VL - 192
SP - 86
EP - 99
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
IS - 1
ER -