Cholesterol hypercholesterolemia

Another demonstrable effect of thyroid hormones is their stimulation of the biosynthesis of bile acids from hepatic cholesterol. Hypercholesterolemia is known to accompany... 

Hyperlipidemia increase in lipids either increase in cholesterol (Hypercholesterolemia), in glycerides (Hyperglyceridemia) or in triglycerides (Hypertriglyceridemia). 

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. 

Denke, M. A., 1995. Lack of efficacy of low-dose sitostanol therapy as an adjunct to a cholesterol-lowering diet in men widi moderate hypercholesterolemia. American Journal of Clinical Nutrition 61 392—396. 

The bile acid sequestrants are used as adjunctive therapy for the reduction of elevated serum cholesterol in patients with hypercholesterolemia who do not have an... 

Some patients, in particular those with genetic forms of hypercholesterolemia (Table 9-2), will require three or more drugs to manage their disorder. Regimens using a statin, resin, and niacin were found to reduce LDL cholesterol up to 75%.42 These early studies were conducted with lovastatin, so larger reductions would be expected with the more potent statins available today. 

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. 

Currently, there are a number of systemic and intestine-selective MTP inhibitors, including lomitapide (23, BMS-201038, AEGR-733), implitapide (24), JTT-130, SLx-4090, and R-256918 (latter three structures not disclosed) believed to be in active development [60]. In a meta-analysis of three Phase II clinical trials, lomitapide as monotherapy or in combination with ezetimibe, atorvastatin, or fenofibrate significantly reduced LDL cholesterol (up to 35% as monotherapy and 66% in combination with atorvastatin) and was well tolerated with less than 2% discontinuation due to abnormal liver function [61]. Lomitapide has also been granted orphan drug status for the treatment of homozygous familial hypercholesterolemia [59]. Results of a Phase II study of JTT-130 for type 2 diabetes are expected in August 2010 [59,60]. 

Bobek P, Ozdin L and Hromadova M. 1998. The effect of dried tomato, grape and apple pomace on the cholesterol metabolism and antioxidative enzymatic system in rats with hypercholesterolemia. Nahrung 42(5) 317— 320. 

A 45-year-old male takes simvastatin for hypercholesterolemia however, his cholesterol level remains above target at maximal doses. Cholestyramine is added to the therapeutic regimen. What drug-drug interaction can occur ... 

A 40-year-old male with markedly elevated cholesterol, diagnosed as having heterozygous familial hypercholesterolemia, is treated with cholestyramine. What is the mechanism of action of cholestyramine ... 

The answer is a. (Katzung, p 590.) Bile acids are absorbed primarily in the ileum of the small intestine. Cholestyramine binds bile acids, preventing their reabsorption in the jejunum and ileum. Up to 10-fold greater excretion of bile acids occurs with the use of resins. The increased clearance leads to increased cholesterol turnover of bile acids. Low-density lipoprotein receptor upregulation results in increased uptake of LDL. This does not occur in homozygous familial hypercholesterolemia because of lack of functioning receptors. 

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. 

Familial hypercholesterolemia is characterized by a selective elevation in plasma LDL and deposition of LDL-derived cholesterol in tendons (xanthomas) and arteries (atheromas). 

In addition to the frequency considerations attendant to the examination of polymorphisms or haplotypes, one must also consider the impact of possible differences in the magnitude of effects of any putative loci. The magnitude of any effects is denoted as "scale" effects based on the notion from quantitative genetics that there will be a displacement from the overall population mean for a trait that is dependent on genotype. To illustrate the effects of scale and frequency, consider two well-known examples of genetic effects. These are the effect of the apolipoprotein E (apo E) polymorphism on cholesterol levels and the impact of the familial hypercholesterolemia polymorphism on cholesterol levels. 

Erotein whether or not cholesterol was added to the diets C3) ince the publication of this experiment over 45 years ago, there has been a recent resurgence of interest in the area of protein effects on plasma lipids and atherosclerosis. This paper summarizes some of the data generated in our laboratory over the last several years and discusses their significance in relation to hypercholesterolemia and atherosclerosis in other species including humans. 

The standard diet used in our experiments is a semipurified, cholesterol-free preparation that is composed of 25% protein, 40% sucrose, 13% coconut oil, 1% corn oil, 15% cellulose, 5% mineral mix, and 1% vitamin mix. This diet has been shown to induce an endogenous hypercholesterolemia and lead to atherosclerosis in rabbits and monkeys (4, 5). The specific question addressed by our series of investigations is whether the type of dietary protein, when all other dietary components are constant, can influence the development of hyperlipoproteinemia and atherosclerosis. More specifically, we have examined the effects of the individual amino acids, lysine and arginine, and their ratios in the diet on plasma and hepatic lipids as well as the development of arterial plaques. 

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