Cannabinoids impair the formation of cholesteryl ester in cultured human cells.

The ability of cultured human fibroblasts to form cholesteryl esters from 14C-oleate is impaired by delta'-tetrahydrocannabinol, cannabidiol, and cannabinol, a group of natural products isolated from Cannabis sativa. This inhibition is compound and dose-related; 30 microM cannabidiol reduced esterification to less than 20% of the control values. The esterification of endogenous and exogenous cholesterol was affected, since inhibition was seen with either low density lipoproteins (200 micrograms/ml) or 25-hydroxycholesterol (5 micrograms/ml) as esterification stimuli. Cells treated with these compounds at doses of from 1 to 30 microM showed no impairment of protein synthesis, triglyceride or phospholipid formation, or ability to metabolize 125I-low density lipoproteins. An inhibition of cholesterol esterification was seen in human aortic medial cells. With increasing doses of these compounds, low density lipoproteins (25 micrograms/ml) became progressively less effective in suppressing HMG-CoA reductase in cultured human fibroblasts; with 30 microM cannabidiol the enzyme suppression was only 24% of that found in cells incubated with low density lipoproteins in the absence of drugs. Based on these data, we conclude that the cannabinoids "compartmentalize" cholesterol and, thus, make is unavailable for regulating cellular cholesterol metabolism. This may occur as a result of enhanced sterol efflux.

Heterozygous defects in alpha 1-antitrypsin and low-density lipoprotein receptor. Simultaneous occurrence in a pediatric patient.

alpha 1-Antitrypsin is a serum protein protease inhibitor. The homozygous deficiency state for alpha 1-antitrypsin is associated with the development of chronic obstructive lung disease and liver cirrhosis. Familial hypercholesterolemia is a genetic defect in which the nonhepatic tissues of affected persons are partially or completely deficient in cellular receptors for low-density lipoproteins, the major plasma cholesterol transport protein. Homozygotes and heterozygotes for familial hypercholesterolemia experience premature coronary artery disease. We have identified a young patient who manifested heterozygous deficiencies for both of these gene products. The occurrence of these defects in tandem has not been previously reported.