Mechanism of inhibition of cholesterol uptake by the arterial wall.

Experiments have been described dealing with lipid synthesis and cholesterol uptake in perfused human and pig coronary arteries, rabbit aortas, and with the inhibitory effect of 7-ketocholesterol on cholesterol uptake in these preparations and in rabbits in vivo. Human and pig coronary arteries failed to synthesize cholesterol in vitro. 7-ketocholesterol inhibited cholesterol uptake in human coronary arteries and aortas of pigs and rabbits in vitro and by rabbit aortas in vivo. The inhibitory effect in vivo could only be shown after repeated i.v. injections of 7-ketocholesterol after solubilizing the steroid with bile sale (Na-glycocholate). Although 7-ketocholesterol was absorbed from the G.I. tract, gastric feeding of the bile salt steroid complex was ineffective, probably because of inadequate blood levels of 7-ketocholesterol achieved. The metabolic fate of 7-ketocholesterol and the nature of its effect on cholesterol are discussed. It is not likely that inhibition of HMG-CoA reductase is responsible for the inhibition of cholesterol uptake. The possibility was discussed that both cholesterol and 7-ketocholesterol actively compete for identical and specific binding sites or that an increase in 7-ketocholesterol in plasma leads to an increase in intracellular concentrations of this steroid thus inhibiting cholesterol transfer across the cell membrane. However definite conclusions on the nature of inhibition must await further experimentation.