LDL-cholesterol complex

The LDL-cholesterol complex binds to LDL receptors on the cell surfaces.167 168 200-202 These receptors are specific for apolipoprotein B-100 present in the LDL. The occupied LDL-receptor complexes are taken up by endocytosis through coated pits the apolipopro-teins are degraded in lysosomes, while the cholesteryl... 

There are two types of complexes low-density (LDL), which contain mostly cholesterol, and high-density (HDL), which contain relatively little cholesterol. Commonly, these complexes are referred to as "LDL cholesterol" and "HDL cholesterol." respectively. 

Cholesterol, triglycerides, and phospholipids are transported in the bloodstream as complexes of lipid and proteins known as lipoproteins. Elevated total and LDL cholesterol and reduced HDL cholesterol are associated with the development of coronary heart disease (CHD). 

The primary defect in familial hypercholesterolemia is the inability to bind LDL to the LDL receptor (LDL-R) or, rarely, a defect of internalizing the LDL-R complex into the cell after normal binding. This leads to lack of LDL degradation by cells and unregulated biosynthesis of cholesterol, with total cholesterol and LDL cholesterol (LDL-C) being inversely proportional to the deficit in LDL-Rs. 

Mechanism of Action An antihyperlipoproteinemic that binds with bile acids in the intestine, forming an insoluble complex. Binding results in partial removal of bile acid from enterohepatic circulation. Therapeutic Effect Removes LDL cholesterol from plasma. 

After binding, the LDL-receptor complex is internalized by endocytosis. [Note A deficiency of functional LDL receptors causes a significant elevation in plasma LDL and, therefore, of plasma cholesterol. Patients with such deficiencies have type II hyperlipidemia (familial hypercholesterolemia) and premature atherosclerosis. The thyroid hormone, T3, has a positive effect on the binding of LDL to its receptor. Consequently, hypothyroidism is a common cause of hypercholesterolemia.]... 

Recently the means by which pectin lowers cholesterol levels and even the validity of this effect have been questioned. Upon finding no bile salt binding capacity for soluble pectin, Baig and Cerda (76) proposed that pectin lowered serum cholesterol levels by forming insoluble complexes with the serum low density lipoproteins (LDL) which transport circulating cholesterol. Complexing of LDL by citrus pectin was observed in vitro, but the way in which pectin or some component thereof enters the blood stream to effect such binding in vivo has not been determined. 

Rabbits fed a 0.5% cholesterol diet had atherosclerotic plaques on over 50%i of the aorta surface whereas the 0.5% cholesterol plus 40 mg lignan complex/kg body/per day reduced atherosclerosis by 34.4% (Prasad, 2005). Furthermore, the added lignan complex lowered the total cholesterol, LDL cholesterol, serum, and aortic malondialdehyde by 20%, 14%, 35%, and 58%, respectively. Unlike previous studies, the lignan enhanced HDL cholesterol by 25% and 30% in normocholesterolemic and hypercholesterolemic rabbits, respectively. Slightly higher (33% and 35%) reductions in total cholesterol and LDL cholesterol, respectively, were observed in rabbits on a 1% cholesterol diet containing 15 mg SDG/kg/day (Prasad, 1999). A 73% reduction in atherosclerosis was observed in the rabbits given the SDG diets compared to the 1% cholesterol diets. 

Saponins appear to lower plasma LDL cholesterol concentration by interfering with cholesterol absorption. Studies in rats and monkeys fed naturally occurring saponins exhibited significant reductions in cholesterol absorption efficiency and an increase in fecal cholesterol excretion (Malinow et al., 1981 Nakamura et al., 1999 Sidhu et al., 1987). Decreased bile acid absorption and increased excretion has also been reported in animals fed saponins (Malinow et al., 1981 Nakamura et al., 1999 Stark and Madar, 1993). One possible mechanism of action for decreased cholesterol absorption is the ability of saponins to form insoluble complexes with cholesterol (Gestetner et al., 1972 Malinow et al., 1977). In an effort to isolate the specific properties of saponins, Malinow (1985) prepared a variety of synthetic saponins in which the complex carbohydrate moieties of native plant saponins were replaced with simplified carbohydrates such as glucose or cellobiose. One of these synthetic saponins, tiqueside (Pfizer, Inc.), can effectively precipitate cholesterol from micelle solutions in vitro and inhibit cholesterol absorption in a variety of animals (Harwood et al., 1993) and in humans (Harris et al., 1997). But despite ample data showing the formation of a saponin/cholesterol complex in vitro, there is essentially no definitive evidence that complexation occurs in the intestinal lumen (Morehouse et al., 1999). 

LDL binds specifically to lipoprotein receptors on the cell surface. The resulting complexes become clustered in regions of the plasma membrane called coated pits. Endocytosis follows (see Fig. 13-3). The clathrin coat dissociates from the endocytic vesicles, which may recycle the receptors to the plasma membrane or fuse with lysosomes. The lysosomal proteases and lipases then catalyze the hydrolysis of the LDL-receptor complexes the protein is degraded completely to amino acids, and cholesteryl esters are hydrolyzed to free cholesterol and fatty acid. New LDL receptors are synthesized on the endoplasmic reticulum (ER) membrane and are subsequently reintroduced into the plasma membrane. The cholesterol is incorporated in small amounts into the endoplasmic reticulum membrane or may be stored after esterification as cholesteryl ester in the cytosol this occurs if the supply of cholesterol exceeds its utilization in membranes. Normally, only very small amounts of cholesteryl ester reside inside cells, and the majority of the free cholesterol is in the plasma membrane. 

Fig. 13-3 The fate of LDL-receptor complexes in cholesterol uptake into cells.

Although increased plasma LDL cholesterol is indicative of the heterozygous form of FH, it is not sufficient to make the diagnosis. Other more complex laboratory tests, such as the demonstration of decreased LDL receptor activity or the confirmation of a mutation in the LDL receptor gene, are necessary to confirm the presence of this disease. However,... 

In a fifth method (International Reagents Corp., Kokusai-Kobe, Japan), its first reagent contains the detergent cal-ixarene that converts LDL to a soluble complex. Cholesterol esters of HDL-C and VLDL-C are preferentially hydrolyzed by a cholesterol esterase (chromobacterium), cholesterol oxidase, and hydrazine, which divert the accessible cholesterol to cholestenone hydrazone. A second reagent with deoxycholate brealcs up the LDL-calixarene complex, allowing LDL-C to react with the esterase, a dehydrogenase, and P-NAD to yield cholestenone and fi-NADH, the latter measured by a spectrophotometer. 

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