Cholesterol, 7-ketocholesterol and 25-hydroxycholesterol uptake studies and effect on 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity in human fibroblasts.

In human fibroblasts two oxidized derivatives of cholesterol, 7-ketocholesterol and 25-hydroxycholesterol, but not cholesterol itself, are potent inhibitors of 3-hydroxy-3-methylglutaryl co-enzyme A reductase (mevalonate: NADP+ oxidoreductase (Co-enzyme A acylating), (EC 1.1.1.34), the rate-limiting enzyme in sterol biosynthesis. In addition, these derivatives of cholesterol are effective regulators in cells from homozygous familial hypercholesterolemic individuals. The differences in the inhibitory potencies of the sterols cannot be explained in terms of the amount of uptake into the cell.

Circadian periodicity of plasma corticosterone levels in rats subjected to hemorrhagic shock and surgical trauma.

The effects of surgical trauma and hemorrhagic shock on the circadian rhythmicity of corticosteroid secretion in the rat were investigated. The estimations were performed at 4-hour intervals for a 24-hour period. Control animals exhibited a characteristic circadian rhythm of plasma corticosterone with peak concentrations occurring at 8 p.m. followed by a gradual fall during the night, reaching a minimum at 8 a.m. Severe stress induced by hemorrhagic shock or surgical trauma caused a dramatic alteration in corticosterone rhythms which persisted up to 72 h following surgery or hemorrhage. It is apparent that the physiological mechanisms which regulate adrenal rhythmicity are disrupted for a prolonged period following major stress or trauma.

Lipoprotein regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in rat liver cell cultures.

A primary cell culture technique was used to study the effects of lipoproteins on rat hepatocyte 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity. In this system, lipoproteins prepared from normocholesterolemic rat and human plasma, including low density lipoproteins, did not inhibit hepatocyte HMG-CoA reductase activity whereas very low density lipoproteins and high density lipoproteins isolated from the same sources were stimulatory. A lipoprotein was isolated from the plasma of cholesterol-fed rats that did inhibit hepatocyte HMG-CoA reductase activity. An extensive chemical characterization of the inhibitory lipoprotein revealed that it was mainly d less than 1.019 g/ml and had beta mobility on lipoprotein electrophoresis. The lipoprotein was compared to the comparable density fraction in the normocholesterolemic rat plasma and there was no size difference appreciable by negatively stained electron micrographs. However, two important differences in chemical composition were evident: in the inhibitory lipoproteins the per cent of total apoprotein which was in the region of Mr = 35,000 was increased 1.5- to 2-fold, and there was a marked increase in cholesterol ester content. These chemical characteristics may be required for lipoproteins to regulate hepatocyte cholesterol synthesis. Primary cell culture of rat hepatocytes appears to be a useful system in which to study cholesterol metabolism in the liver.