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.

An overview on genus garcinia: phytochemical and therapeutical aspects

“…Hood et al (1985) provided the in vitro inhibitory effect of HCA on the conversion of lactate, acetate and glucose to fatty acids in bovine and rat adipose tissues. HCA also inhibited the incorporation of C 14 labeled citrate into fatty acids and cholesterol in Hep G2 cells after 18 h of incubation (Berkhout et al 1990). These studies suggested the beneficial properties of HCA in the weight management by interfering in the fatty acid biosynthesis and cholesterol homeostasis.…”

AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism

“…Pharmacological inhibition of ACL has been shown to limit sterol and fatty acid synthesis ( 40,(43)(44)(45)(46), upregulate LDL receptor activity ( 47 ), and reduce plasma triglycerides and cholesterol levels ( 45,48 ). Furthermore, liverspecifi c ACL abrogation results in reduced levels of liver Fig.…”

Inhibition of Adrenal Cortical Steroid Formation by Procaine Is Mediated by Reduction of the cAMP-Induced 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Messenger Ribonucleic Acid Levels

“…The supernatant was applied to a Bond-Elut NH 2 column and eluted with 1 ml of toluene/acetone (3:1). The eluate was discarded and an additional 4 ml of toluene/acetone was applied to the column and collected in a scintillation vial for counting 14 C and 3 H signals (Berkhout et al, 1990).…”