Effect of probucol on plasma clearance and organ uptake of chylomicrons and VLDLs in normal and diabetic rats.

Abstract

Probucol was given to rats made diabetic by streptozotodn. Compared with diabetic rats not receiving probucol or with nondiabetic rats, probucol lowered the plasma concentrations of trigrycerkies, phospholipids, cholesterol, and apolipoproteln B. The concentrations of serum chylomicrons and very low density lipoprotein (VLDL) were also reduced. In control and diabetic rats, probucol enhanced the clearance of endogenoushy radiolabeled VLDL from the plasma. Clearances from the plasma of rat lymph chylomicrons or chylomicronlike lipkJ emulsions were slow in diabetic rats. Probucol normalized chyiomicron clearance in diabetic rats primarily by restoring hepatic uptake of remnants, which was decreased in diabetes. In diabetic rats, uptake of chyiomicron remnants was increased in a number of extrahepatic tissues, including the heart and kidney. Probucol significantly decreased uptake in some extrahepatic tissues. Increased plasma clearance of VLDL and chylomicrons was associated with an increase in the apolipoprotein CH/Clll and apolipoprotein E/C ratios. Orally administered probucol was specifically incorporated into lymph chylomicrons, and clearance of probucol from the plasma exactly paralleled the clearance of chyiomicron remnants, as traced with radiolabeled cholesteiyl esters. Chylomicron-like emulsions incorporating probucol were exclusively cleared from the plasma by the liver in normal rats. We conclude that in streptozotodn diabetic rats, probucol is an effective hypolipidemic agent because it promotes the clearance of the trigiyceride-rich lipoproteins. are frequently found in patients with diabetes mellitus. The hyperlipidemia primarily reflects slow clearance of plasma lipoproteins, although overproduction of lipoproteins may also be a contributing factor in non-insulin-dependent diabetes.1 A defective clearance from the plasma of chylomicrons and very low density lipoproteins (VLDLs) has been reported in human diabetic patients (for a review, see Howard 1 ) and in animal models of this disease.2 " 4 Hydrolysis of triglycerides may be compromised by severe insulin deficiency because insulin maintains the synthesis and secretion of lipoprotein lipase in some tissues.5 Posthydrolysis clearance of the remnant particles is also delayed, 6 although the reasons for this are unclear. Elevated plasma concentrations of triglycerides and cholesterol are thought to contribute to the high incidence of atherosclerosis in diabetic patients, and so it is desirable to reduce the concentrations of these lipids. Probucol is a potent hypolipidemic agent that reduces serum cholesterol level principally by increasing the fractional catabolic rate of low density lipoprotein (LDL). 7 ? Probucol is an effective lipid antioxidant, but it is not clear whether its pharmacological actions on the metabolism of LDL are related to the prevention of oxidation. Lipoproteins from diabetic donors show increased amounts of oxidative products compared with lipoproteins of nondiabetic origin. Probucol has been shown to decrease oxidation of...

Antioxidant treatment of experimental diabetic retinopathy in rats with nicanartine

“…Results from this study should not be extrapolated to human diabetes without caution, especially due to the more severe diabetic state of the animals studied and to the differences in lipid metabolism between rodents and humans [41,42]. With the development of stronger antioxidant compounds which preferably should be targeted to interfere with increased intracellular oxidative stress, we anticipate that the true role of oxidation in the pathogenesis of diabetic retinopathy is assessable.…”

Alterations in liver sinusoidal endothelium in a baboon model of type 1 diabetes

“…However, defenestration associated with old age [9] and treatment with a surfactant, poloxamer 407 [27], are associated with impaired transfer of lipoproteins and hypertriacylglycerolaemia. Delayed chylomicron remnant clearance and subsequent post-prandial hypertriacylglycerolaemia are features of type 1 diabetes [10][11][12]; thus it is possible that the substantial loss of fenestrations may contribute to this dyslipidaemia.…”

“…This provides a mechanism for age-related impairment in chylomicron remnant clearance and post-prandial hypertriacylglycerolaemia, thus possibly contributing to enhanced vascular risk among older people [4]. As such, there are potential parallels with dyslipidaemia in patients with diabetes mellitus [10][11][12].…”

Probucol Suppresses Enterocytic Accumulation of Amyloid‐β Induced by Saturated Fat and Cholesterol Feeding

“…Probucol is an older generation cholesterol-lowering agent that reduces plasma cholesterol by enhancing uptake via receptor pathways [23,24]. However, other properties of Probucol make this a particularly interesting lipid lowering agent relative to the plasma kinetics and metabolism of apo B-lipoprotein-A.…”