Abstract
The control of hyperlipidemia plays a central role in cardiovascular disease. Previously, we have shown that camphene, a constituent of mastic gum oil, lowers cholesterol and triglycerides (TG) in the plasma of hyperlipidemic rats without affecting HMG-CoA reductase activity, suggesting that its hypocholesterolemic and hypotriglyceridemic effects are associated with a mechanism of action different than that of statins. In the present study, we examine the mechanism by which camphene exerts its hypolipidemic action. We evaluated the effect of camphene on the de novo synthesis of cholesterol and TG from [14C]-acetate in HepG2 cells, along with the statin mevinolin. Camphene inhibited the biosynthesis of cholesterol in a concentration-dependent manner, and a maximal inhibition of 39% was observed at 100 μM while mevinolin nearly abolished cholesterol biosynthesis. Moreover, treatment with camphene reduced TG by 34% and increased apolipoprotein AI expression. In contrast, mevinolin increased TG by 26% and had a modest effect on apolipoprotein AI expression. To evaluate the mode of action of camphene, we examined its effects on the expression of SREBP-1, which affects TG biosynthesis and SREBP-2, which mostly affects sterol synthesis. Interestingly, camphene increased the nuclear translocation of the mature form of SREBP-1 while mevinolin was found to increase the amount of the mature form of SREBP-2. The effect of camphene is most likely regulated through SREBP-1 by affecting MTP levels in response to a decrease in the intracellular cholesterol. We propose that camphene upregulates SREBP-1 expression and MTP inhibition is likely to be a probable mechanism whereby camphene exerts its hypolipidemic effect.
Highlights
High levels of plasma cholesterol and triglycerides are strongly associated with the development of atherosclerosis and coronary heart disease (CHD) [1,2,3,4]
We have previously shown that camphene, a plant monoterpene derived from chios mastic gum oil (MGO), decreases serum total cholesterol, Low Density Lipoprotein (LDL) cholesterol and triglyceride levels in hyperlipidemic rats [12]
We found that camphene treatment reduced fatty acid, triglyceride as well as cholesterol de novo biosynthesis in HepG2 cells and had an effect on apolipoprotein AI (apoAI) protein levels, the major component of High Density Lipoprotein (HDL), and SREBP transcription factors, the master regulators of genes that are responsible for lipid biosynthesis
Summary
High levels of plasma cholesterol and triglycerides are strongly associated with the development of atherosclerosis and coronary heart disease (CHD) [1,2,3,4]. In addition to testing new approaches to LDL cholesterol lowering there has been a major focus on treatments that can favorably influence High Density Lipoprotein (HDL) and triglycerides concentrations. Alternative approaches to treat dyslipidemia are being developed and are based on the inhibition of enzymes involved in lipid metabolism such as Acyl-CoA:cholesterol acyltransferase (ACAT), microsomal triglyceride transfer protein (MTP), 2,3-oxidosqualene:lanosterol cyclase (OSC), cholesteryl ester transport protein (CETP) and others [10, 11]. We have previously shown that camphene, a plant monoterpene derived from chios mastic gum oil (MGO), decreases serum total cholesterol, LDL cholesterol and triglyceride levels in hyperlipidemic rats [12]. The lipid-lowering action of camphene was found to be independent of HMG-CoA reductase activity, suggesting that the hypolipidemic effects of camphene are mediated through a mechanism of action different to that of statins [12]. The purpose of this study was to further investigate the molecular mechanism of the hypolipidemic activity of camphene
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