Experimental hypothyroidism modulates the expression of the low density lipoprotein receptor by the liver.

The effect of experimental hypothyroidism on the catabolism of plasma lipoproteins and on the expression of low density lipoprotein receptors by the liver was investigated in rats made hypothyroid by surgery. The animals developed mild hypercholesterolemia, mainly due to an increase of plasma low density lipoprotein, while other lipoprotein classes were only marginally affected. Kinetic studies using [125I]LDL indicated that a decreased fractional catabolic rate of the lipoprotein was responsible for this finding in agreement with the in vitro observation of a reduced binding of lipoproteins to liver membranes from hypothyroid rats and with the demonstration, by ligand blotting analysis, of a decreased expression of lipoprotein receptors in liver membranes. These data suggest that hypothyroidism affects lipoprotein distribution also by decreasing the catabolism of low density lipoproteins by the liver.

Effects of probucol on the in vivo plasma clearance of human low density lipoproteins in rabbits and on the expression of lipoprotein receptors in vitro.

The purpose of this study was to investigate the effects of probucol on the plasma levels of low density lipoproteins in rabbits and whether the resulting decrease of low density lipoproteins was related to the effects of probucol on the expression of lipoprotein receptors. Probucol administration effectively lowered plasma cholesterol in normal rabbits. Both low density and high density lipoprotein cholesterol decreased, as well as apo B in the former fraction. Probucol had no effect on the fractional catabolic rate of low density lipoprotein while the flux of this lipoprotein decreased to about 50%. Moreover both the binding of lipoproteins to liver membranes and the in vitro uptake of low density lipoprotein by human skin fibroblasts were not affected by the drug. These findings are consistent with an effect of probucol on low density lipoprotein synthesis.

Effect of partial ileal bypass on plasma clearance and binding of lipoproteins to liver membranes in the rabbit.

We studied the effect of partial ileal bypass in the rabbit on the in vivo catabolism of human 125I-labelled low density lipoproteins and on the in vitro binding of human low density lipoproteins and rabbit very low density lipoproteins to hepatic membrane preparations. The in vivo data indicate that partial ileal bypass increases the fractional clearance rate (pools/h) of low density lipoproteins from 0.031 to 0.049 as well as the absolute catabolic rate from 0.495 to 0.605 mg/h. Concomitantly the in vitro binding of both low and very low density lipoproteins to hepatic membranes was increased in membrane preparation from livers of bypassed animals, thus suggesting an increased receptor-mediated uptake of lipoproteins by the liver. This effect may partly explain the hypocholesterolemic activity of partial ileal by-pass.

In vivo assimilation of low density lipoproteins by a fibrosarcoma tumour line in mice.

A tumour line inoculated in mice showed high affinity binding for lipoproteins in vitro. Studies in vivo demonstrated that the assimilation of human low density lipoprotein (LDL) by the tumour was very high. Both receptor and non-receptor mediated catabolism of the lipoprotein by the tumour increased as compared to other tissues known to be sites of lipoprotein catabolism (liver, spleen etc.). These findings suggest that lipoproteins may be useful markers for tumours as well as carriers for cytotoxic drugs to target tissues in vivo.

beta-Adrenergic receptors in brain microvessels of diabetic rats.

A significant decrease in the number of beta-adrenergic receptors was observed in cerebral microvessels of fatty (fa/fa) and streptozotocin-induced diabetic rats, without receptor affinity changes. These results suggest that alterations of central adrenergic regulation of small vessels may be involved in brain microvasculature disturbances that occur with diabetes.

Effects of insulin deficiency on the catabolism of plasma lipoproteins and on the expression of hepatic lipoprotein receptors in rats.

The effect of insulin deficiency on the expression of lipoprotein receptors by the liver and on the in vivo catabolism of plasma lipoproteins was investigated in rats made insulin deficient by an I.V. injection of streptozotocin. The binding of beta very low density lipoprotein to liver membranes was not affected by insulin deficiency, furthermore the in vivo catabolism of beta very low density lipoproteins and low density lipoprotein in diabetic rats was similar to that of controls. These data suggest that insulin deficiency neither modulates the expression of receptors for lipoproteins by the liver nor the in vivo catabolism of lipoproteins such as beta very low density and low density lipoproteins which are removed from the plasma, at least in part, by receptor mediated processes.

Subfractionation of human very low density lipoproteins by heparin-Sepharose affinity chromatography.

Very low density lipoproteins obtained from normolipidemic subjects were fractionated into subclasses by means of affinity chromatography on a heparin-Sepharose column in the presence of MnCl2. The four subfractions eluted at 0.05, 0.12, 0.20, and 0.38 M NaCl and they differed in chemical composition and apoprotein pattern. The relative amounts of apoB and apoE in subfractions increased with increasing concentrations of the NaCl eluant. Modification of the arginyl residues with 1-2 cyclohexadione demonstrated that arginine plays an important role in determining the elution pattern of VLDL. In vitro studies indicated that only fractions eluted at 0.2 and 0.5 M NaCl compete with LDL for cellular receptors. These data suggest that the various subfractions may represent VLDL at different stages of catabolism.

A saturable binding site for high density lipoprotein3 on human liver membranes.

The binding of High Density Lipoprotein3 (HDL) to human liver membranes obtained from male normolipemic subjects was studied. High Density Lipoprotein3 binds in a specific, saturable manner to liver membranes; furthermore, this binding site appears to be distinct from these previously described for Low Density Lipoprotein (LDL) and chylomicron remnants. Competition experiments using Apo A-I reconstituted lipoproteins suggest that Apo A-I could be the determinant of the binding.

Experimental studies on the hypolipidemic activity of chloridarol.

The efficacy of chloridarol (2-benzofuryl-p-chlorophenyl carbinol) as hypolipidemic agent was evaluated in rats and rabbits. In normolipidemic rats chloridarol, at doses ranging from 50 to 200 mg/kg/day, decreased plasma triglycerides without affecting cholesterolemia and fast- or norepinephrine-induced lipolysis. The drug proved effective in reducing fructose-induced hypertriglyceridemia and dietary hypercholesterolemia in rats; in the latter model chloridarol significantly raised both the HDL cholesterol and the HDL/VLDL + LDL cholesterol ratio. In hyperlipidemic rabbits the drug had no effect on plasma cholesterol, but it lowered triglyceridemia. The action of chloridarol on rat liver ultrastructure was also investigated. Treatment for one month induced peroxisome proliferation, less marked, however, than that elicited by clofibrate; after a prolonged chloridarol treatment (9 months), this effect had almost completely disappeared and the ultrastructure of the hepatocytes was close to that of controls.