Cholesterol diseases resulting from

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. 

Serious Diseases Result from Cholesterol Deposits High-Density Lipoproteins (HDLs) May Reduce Cholesterol Deposits... 

Serious Diseases Result from Cholesterol Deposits... 

Mass spectrometry has become an indispensable method for the analysis of bile acids by virtue of its power to identify, assign structure and quantify free or conjugated bile acids, either pure or in mixtures. It is useful not only to study the metabolism of bile acids but also for the detection and diagnosis of metabolic diseases. Indeed, numerous metabolic diseases resulting from an alteration of the conversion of cholesterol to bile acids have been described, including peroxisomal disorders resulting in a block of (3-oxidation of the lateral chain and other enzyme deficiencies interfering with the biochemistry of the side chain or the steroid nucleus. 

Two genetically determined disorders, familial HDL deficiency and Tangier disease, result from mutations in the ATP-binding cassette 1 (ABC 1) protein. Cholesterol-depleted HDL cannot transport free cholesterol from cells that lack the ability to express this protein. As a consequence, HDL is rapidly degraded. These disorders have established a role for ABC 1 protein in the regulation of HDL levels in the blood. 

Heart disease is any condition that diminishes the hearts ability to pump blood. A common heart disease is arteriosclerosis, a buildup of plaque on the inside walls of arteries. As discussed in Section 13.8, plaque deposits are mostly an accumulation of low-density lipoproteins, which are high in cholesterol and saturated fats. Plaque-filled arteries are less elastic and have a decreased volume. Both these effects make pumping blood more difficult, and the heart becomes overworked and weakens. Accumulated damage to heart muscle from arteriosclerosis or other stresses can result in abnormal heart rhythms, known as arrhythmia. Chest pains, known as angina, result from an insufficient oxygen supply to heart muscles. Ultimately, the weakened heart does not adequately circulate blood to the body. People with heart disease have decreased stamina and frequently need to catch their breath. 

Familial hypercholesterolemia results from a defective LDL receptor. As a result, the cholesteryl ester in the LDL of the bloodstream cannot be cleared by the normal process, hence, high cholesterol levels occur in the plasma of these patients. Somehow, the high levels of cholesterol lead to the formation of the atherosclerotic lesions, the underlying cause of premature heart disease in these patients. 

Of the many disorders of lipoprotein metabolism (Tables 5.2 and 5.3), familial hypercholesterolaemia type II may be the most prevalent in the general population. It is an autosomal dominant disorder that results from mutations affecting the structure and function of the ceU-surface receptor that binds plasma LDLs and removes them from the circulation. The defects in LDL-receptor interaction result in lifelong elevation of LDL cholesterol in the blood. The resultant hypercholesterolaemia leads to premature coronary artery disease and atherosclerotic plaque formation. Familial hypercholesterolaemia was the first inherited disorder recognised as being a cause of myocardial infarction (heart attack). 

Atherosclerosis is a disease that results from the buildup of fatty deposits on the walls of arteries, forming deposits called plaque. They are composed largely of the cholesterol (esterified as an ester) of LDL particles. LDL is often referred to as bad cholesterol for this reason. In contrast, HDL particles are called good cholesterol because they reduce the amount of cholesterol in the bloodstream by transporting it back to the liver. 

Apo E consists of 299 amino acids. A genetic disease, called type 111 hyperlipoproteinemia, results from naturally occurring mutations in the apo E gene. The disease results in high plasma cholesterol, high plasma TCs, premature atherosclerosis, and xanthomas. Xanthomas arc lumpy accumulations of choles terol in the wrists, elbows, knees, and other parts of the body. The most common mutation is one that results in the conversion of Arg 158 to Cys 158 (Lohse el al., 1991). Other naturally crecurring mutations result in a truncated polypeptide, or in the complete absence of apo E,... 

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