Unknown

Dataset Information

0

The effect of (-)-hydroxycitrate on the activity of the low-density-lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase levels in the human hepatoma cell line Hep G2.


ABSTRACT: (-)-Hydroxycitrate, a potent inhibitor of ATP citrate-lyase, was tested in Hep G2 cells for effects on cholesterol homoeostasis. After 2.5 h and 18 h incubations with (-)-hydroxycitrate at concentrations of 0.5 mM or higher, incorporation of [1,5-14C]citrate into fatty acids and cholesterol was strongly inhibited. This most likely reflects an effective inhibition of ATP citrate-lyase. Cholesterol biosynthesis was decreased to 27% of the control value as measured by incorporations from 3H2O, indicating a decreased flux of carbon units through the cholesterol-synthetic pathway. After 18 h preincubation with 2 mM-(-)-hydroxycitrate, the cellular low-density-lipoprotein (LDL) receptor activity was increased by 50%, as determined by the receptor-mediated association and degradation. Measurements of receptor-mediated binding versus LDL concentration suggests that this increase was due to an increase in the numbers of LDL receptors. Simultaneously, enzyme levels of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase as determined by activity measurements increased 30-fold. Our results suggest that the increases in HMG-CoA reductase and the LDL receptor are initiated by the decreased flux of carbon units in the cholesterol-synthetic pathway, owing to inhibition of ATP citratelyase. A similar induction of HMG-CoA reductase and LDL receptor was also found after preincubations of cells with 0.3 microM-mevinolin, suggesting that the underlying mechanism for this induction is identical for both drugs.

SUBMITTER: Berkhout TA 

PROVIDER: S-EPMC1149674 | biostudies-other | 1990 Nov

REPOSITORIES: biostudies-other

Similar Datasets

| S-EPMC1144140 | biostudies-other
| S-EPMC1135190 | biostudies-other
| S-EPMC1147567 | biostudies-other
| S-EPMC1152337 | biostudies-other
| S-EPMC4094470 | biostudies-literature
| S-EPMC6349912 | biostudies-literature
| S-EPMC8214791 | biostudies-literature
| S-EPMC2720070 | biostudies-literature
| S-EPMC3360009 | biostudies-literature
| S-EPMC1138738 | biostudies-other