Hypercholesterolemia LDL receptor

Defects in the LDL receptor have been particularly well explored as a basis of the disease familial hypercholesterolemia (93,111). A number of defects that collectively impair LDL receptor trafficking, binding, or deUvery underHe this disease where LDL and semm cholesterol rise to levels that mediate early cardiovascular mortaUty. Studies of the population distribution of this defect can determine the source of the original mutation. Thus, in Quebec, about 60% of the individuals suffering from familial hypercholesterolemia have a particular 10-kdobase deletion mutation in the LDL gene (112). This may have arisen from an original founder of the French Canadian settiement in the seventeenth century. 

LDL receptor Loss-of-function (familial, autosomal dominant) Familial hypercholesterolemia (impaired clearance of LDL)... 

The hver and many extrahepatic tissues express the LDL (B-lOO, E) receptor. It is so designated because it is specific for apo B-IOO but not B-48, which lacks the carboxyl terminal domain of B-lOO containing the LDL receptor ligand, and it also takes up lipoproteins rich in apo E. This receptor is defective in familial hypercholesterolemia. Approximately 30% of LDL is de-... 

Famiiiai hyperchoiesteroiemia (type iia) Defective LDL receptors or mutation in ligand region of apo B-100. Elevated LDL levels and hypercholesterolemia, resulting in atherosclerosis and coronary disease. 

Familial hypercholesterolemia (MIM 143890) Mutations in the gene encoding the LDL receptor... 

Familial hypercholesterolemia (FH) is an autosomal dominantly inherited disease caused by mutations in the gene for the LDL receptor. Up to now more than 680 distinct mutations, distributed over the entire gene, have been described [42]. Heterozygous FH individuals express only half the number of functional LDL-r and, therefore, have a markedly raised plasma cholesterol and usually present with premature coronary artery disease. Homozygous FH individuals are more severely affected and may succumb before the age of maturity. The prevalence of heterozygous FH is approximately 1 in 500 in Caucasians. 

Karayan L, Qiu S, Betard C, Dufour R, Roederer G, Minnich A, et al. Response to HMG CoA reductase inhibitors in heterozygous familial hypercholesterolemia due to the 10-kb deletion ( French Canadian mutation ) of the LDL receptor gene. Arteriosder Thromb 1994 14 1258-1263. 

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. 

In patients with familial hypercholesterolemia caused by defective LDL-receptor function, Lp(a) concentration in plasma is reported to be 2.5-3.0 times higher than in matched controls (HI 1, U8). In cultured fibroblasts of these patients, catabolism of Lp(a) and LDL is diminished as compared to controls. In fibroblasts of controls, the catabolism of Lp(a) is slower than that of LDL (F13, HI 1, Ml). 

Familial hypercholesterolemia (FH), an autosomal dominant disorder of lipoprotein metabolism, is caused by absent or defective LDL receptors. Several studies indicated that Lp(a) levels were approximately doubled in FH heterozygotes, compared to their unaffected family members or non-FH controls (H30, L14, M20, M21, U8, W13, W14). 

Soutar, A. K., McCarthy, S. N., Seed, M., and Knight, B. L., Relationship between apopro-tein(a) phenotype, lipoprotein(a) concentration in plasma and low-density lipoprotein (LDL) receptor function in a large kindred with Familial Hypercholesterolemia due to the Pro Leu mutation in the LDL-receptor gene. J. Clin. Invest. 88, 483-492 (1991). 

The number of active LDL receptors is also affected by a condition called familial hypercholesterolemia, in which there is a defective gene coding for the receptor. In either case, the reduction of active receptors means that the LDL carrying cholesterol is unable to enter the cell interior instead, it is deposited in the arteries leading to the heart or brain. These deposits build up over time and may block blood supply to the heart muscle or brain, resulting in a heart attack or stroke. In contrast, HDL transports cholesterol from other parts of the body to the liver, where it is degraded to bile acids. 

Treatment of Hypercholesterolemia Cholestyramine and other drugs that increase elimination of bile salts force the liver to increase their synthesis from cholesterol, thus lowering the internal level of cholesterol in the hepatocytes. Decreased cholesterol within the cell increases LDL receptor expression, allowing the hepatocyte to remove more LDL cholesterol from the blood. HMG-CoA reductase inhibitors such as lovastatin and simvastatin inhibit de novo cholesterol synthesis in the hepatocyte, which subsequently increases LDL receptor expression. 

I Coronary heart disease can be caused by mutations in the LDL receptor (familial hypercholesterolemia), inherited cancer syndromes can result from mutations in ... 

Heterozygotes for type 11 hypercholesterolemia have one normal and one mutant LDL receptor gene. Thus, they have just half the normal number of functional hepatic LDL receptors. They are, therefore, less than fully effective at eliminating cholesterol from the body. These individuals have substantially elevated plasma LDL cholesterol levels and frequently experience heart attacks in their 40s and 50s. 

Type II hypercholesterolemia a genetic disease in which the level of hepatic LDL receptors is compromised. 

Homozygous familial hypercholesterolemia HMG-CoA reductase inhibitors are less effective in patients with the rare homozygous familial hypercholesterolemia, possibly because they have no functional LDL receptors. 

Familial hypercholesterolemia (FH) results from inherited deficiency or mutation of the LDL receptor and consequent impairment of uptake and processing of LDL-cholesterol by the liver. 

LDL receptor deficiency leads to extreme hypercholesterolemia and its sequelae by two mechanisms. -Failure to take up cholesterol bound to LDL particles leads to accumulation and consequent elevation of blood LDL cholesterol. 

The answer is D. This patient s tests indicate that he has severe hypercholesterolemia and high blood pressure in conjunction with atherosclerosis. The deaths of several of his family members due to heart disease before age 60 suggest a genetic component, ie, familial hypercholesterolemia. This disease results from mutations that reduce production or interfere with functions of the LDL receptor, which is responsible for uptake of LDL-cholesterol by liver cells. The LDL receptor binds and internalizes LDL-choles-terol, delivers it to early endosomes and then recycles back to the plasma membrane to pick up more ligand. Reduced synthesis of apoproteins needed for LDL assembly would tend to decrease LDL levels in the bloodstream, as would impairment of HMG CoA reductase levels, the rate-limiting step of cholesterol biosynthesis. Reduced uptake of bile salts will also decrease cholesterol levels in the blood. 

Some patients with familial hypercholesterolemia produce a truncated form of the LDL receptor, termed the Lebanese allele, which lacks three of the five domains of the protein and causes it to be retained in the endoplasmic reticulum. Analysis of the mutant gene indicated that the sequence of the protein was normal up to the point where it terminated. 

Polygenic or familial hypercholesterolemia Ila LDL Choi Deficient LDL receptor activity. Abnormal Apo Bioo. High-fat diet, excess calories, inactivity. CHD, stroke... 

D. Reduced hepatic LDL-receptor activity. Familial hypercholesterolemia is most often due to dehcient LDL-receptor activity. A less likely possibility, although not considered in this question, is reduced LDL clearance from the circulation due to defective apolipoprotein Bioo. 

Defects in the domain of apo B-100 that binds to the LDL receptor impair the endocytosis of LDL, leading to hypercholesterolemia of moderate severity. Tendon xanthomas may occur. These disorders are as prevalent as familial hypercholesterolemia. Response to reductase inhibitors is variable. Up-regulation of LDL receptors in liver increases endocytosis of LDL precursors but does not increase uptake of ligand-defective LDL particles. Niacin often has beneficial effects by reducing VLDL production. 

A proper balance of cholesterol in the bloodstream requires having an adequate balance of receptors to process the amount of cholesterol in the blood. Receptors are continually regenerated, produced, and disappear in the cell in response to blood biochemistry. The liver contains the greatest concentration of receptors. Too few receptors or excess dietary cholesterol intake can lead to elevated blood cholesterol. A genetic disorder called familial hypercholesterolemia results when a person inherits a defective gene from one parent resulting in the inability to produce sufficient receptors. A diet with too much cholesterol represses the production of LDL receptors and leads to high blood cholesterol and Apo B. 

Kim SH, Bae JH, Chae JJ, Kim UK, Choe SJ, Namkoong Y, HS, Park YB, Lee CC (1999) Long-distance PCR-based screening for large rearrangements of the LDL receptor gene in Korean patients with familial hypercholesterolemia. Clin Chem 45 1424-1430... 

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