Lipoprotein metabolism, defects

Defects in Lipoprotein Metabolism Can Lead to Elevated Serum Cholesterol... 

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). 

Familial hyperlipoproteinemia Estrogen therapy may be associated with massive elevations of plasma triglycerides leading to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism. 

The decision to use drug therapy for hyperlipidemia is based on the specific metabolic defect and its potential for causing atherosclerosis or pancreatitis. Suggested regimens for the principal lipoprotein disorders are presented in Table 35-2. 

The LDL particles contain one apoB-100 as the structural protein and are the major cholesterol-transporting lipoproteins in human blood. Clearance of LDL from blood is mediated by the interaction of apoB-100 with the LDLR. Genetic defects either in the receptor binding region of apoB-100 or in the LDLR lead to decreased clearance of LDL and hence to their accumulation in the blood. The major metabolic pathways of the lipoprotein metabolism are shown in Fig. 5.2.1. 

Familial hypercholesterolemia (FH) is one of the most common genetic disorders in lipoprotein metabolism, and causes elevated cholesterol levels. This autosomal dominant disorder with a prevalence of about 1/500 in Western countries is caused by mutations in the LDLR gene. The LDLR defect impairs the catabolism of LDL and results in elevation of plasma LDL-cholesterol. Untreated heterozygous FH patients have 2-3 times elevated cholesterol levels and have a 100-fold increased risk to die... 

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). 

Lipoprotein and hepatic lipases are important enzymes involved in the metabolism of chylomicrons and various fractions of lipoproteins. Both have been the subject of attention, as evidenced by numerous reviews (e.g., Garfinkel and Schotz, 1987 Wang eta/., 1992). This interest stems from the fact that abnormal lipoprotein metabolism has been linked to various disorders, including hyperchylomicronemia, hypercholesterolemia, hypertriglyceridemia, obesity, diabetes, and premature atherosclerosis. Genetic defects in both HL and LPL are now known to be the cause of at least some familial disorders of lipoprotein metabolism. 

In type IV hyperlipoproteinemia, levels of VLDL are elevated. Because this type of lipoprotein is rich in triglycerides, plasma iriglyccridc levels arc elevated. The metabolic defect lhat causes type IV is. still unknown this form of hyperlipidemia. however, responds lo diet and drug Iherapy. 

Historically, lipoprotein phenotypes reflecting lipoprotein metabolic disorders were classified according to Fredrickson and co-workers. However, these disorders are more rationally approached based on the four metabolic pathways discussed previously (see Figures 26-18 through 26-21). Defects in these pathways, leading to hyperlipidemia, may be related to (1) increased production of lipoproteins, (2) abnormal intravascular processing (e.g., enzymatic... 

Cholesterol synthesis is essential for normal development and maintenance of tissues that cannot obtain cholesterol from plasma lipoproteins, such as brain [3]. Furthermore, the biosynthetic pathway supplies non-steroidal isoprenoids that are required by all cells. Thus, it is not surprising that metabolic defects in the cholesterol biosynthetic pathway have devastating physiological consequences [8,9]. 

A multitude of genetic defects lead to an increased synthesis and/or a decreased catabolism of cholesterol or LDL. A well characterized although rare defect is the LDL-receptordefect. Ascorbate deficiency unmasks these inherited metabolic defects and leads to an increased plasma concentration of cholesterol-rich lipoproteins, e.g. LDL, and their deposition in the vascular wall. Hypercholesterolemia increases the risk for premature CVD primarily when combined with elevated plasma levels of Lp(a) or triglycerides. 

Fig. 28.1. A schematic diagram depicting lipoprotein metabolism and the known genetic defects affecting lipoproteins. 28.1, Lipoprotein lipase (LPL) deficiency 28.2, apoC-II deficiency 28.3, apoE deficiency or mutations 28.4, hepatic lipase (HL) deficiency 28.5, LDL receptor deficiency or mutations 28.6, apoB-100 mutation in receptor binding region 28.7, apoA-I deficiency or mutations 28.7.3, ABCAl deficiency or mutations 28.8, LCAT deficiency 28.9, microsomal transfer protein (MTP) deficiency 28.10, apoB-100 synthesis or truncation mutations. Abbreviations C-II, apoC-II B, apoB E, apoE A-I, apoA-I VLDL, very-low-density lipoproteins IDL, intermediate-density lipoproteins LDL, low-density lipoproteins HDL, high-density lipoproteins LPL, lipoprotein lipase HL, hepatic lipase LCAT, lecithin cholesterol acyltransferase UC, unesterified cholesterol...

In principle, vitamin E deficiency can resulf from insufficient dietary intake, malabsorption or excessive consumption in case of oxidative stress in biomembranes. While the former is virtually nonexistent in Western society, the impaired ability to utilize dietary fats may create hypovitaminosis E in certain risk populations, e.g., patients with pancreatic dysfunction or defects in lipoprotein metabolism and particularly in premature infants. Deficiency disorders in the latter include bronchopulmonary dysplasia, retrolental fibroplasia (retinopathy), intraventricular hemorrhage, hemolytic anemia, and neuromuscular anomalies. 

The loss of LDL receptor activity readily explains the inefficient clearance of LDL and the hypercholesterolemia of FH patients (Fig. 9). In addition to defective catabolism of LDL, there is also LDL overproduction for the following reason. IDL is also cleared through the LDL receptor. Diminished LDL receptor activity leads to prolonged circulation of IDL, giving it a greater opportunity to be converted to LDL. IDL is at an important branch point in lipoprotein metabolism it can be directly cleared from the circulation or it can be further processed to become LDL. The LDL receptor can also regulate the secretion of VLDL. It promotes reuptake of newly secreted VLDL. Also, within the secretory pathway, the LDL receptor promotes the degradation of newly synthesized apo-BlOO. 

Vitamin E deficiency was first described in children with fat malabsorption syndromes, principally abe-talipoproteinemia, cystic fibrosis, and cholestatic liver disease. Subsequently, humans with severe vitamin E deficiency with no known defect in lipid or lipoprotein metabolism were described to have a defect in the a-TTP gene. 

All of these biological roles of the steroids figure prominently in human well-being. Defects in cholesterol metabolism are major causes of cardiovascular disease. It is no wonder that steroids are a central concern in medical biochemistry. In this chapter we discuss the metabolism of these complex lipids and the plasma lipoproteins in which they and other complex lipids are transported to various tissues. 

Remnant removal disease (RRD, also called remnant lipaemia, familial dysbetalipoproteinemia) (uncommon) in which there is a defect of apolipoprotein E. This is the major ligand that allows internalisation and subsequent metabolism of remnant particles derived from VLDL and chylomicrons. The consequence is accumulation of VLDL remnants called intermediate density lipoprotein (IDL) with cholesterol and triglycerides usually in the range 6-9 mmol/1. Patients experience severe macrovascular disease (as above). 

Berger, G. M. (1986). Clearance defects in primary chylomicronemia A study of tissue lipoprotein lipase activities. Metabolism 35, 1054-1061. 

Atherosclerosis and Plasma Lipids - Lipoprotein lipases play a critical role in the metabolism of lipoproteins and thus may be involved in athero-genesis. Hypercholesterolemia in the cholesterol-fed rabbit was attributed to the accumulation of chylomicron remnants, which may be formed on the aorta wall by lipoprotein lipase and deposited in the deep layers of the arterial wall without prior release into the blood stream.13 On this basis, cholesterol-rich lipoproteins in plasma may be the product rather than the cause of the atherogenic process. However, the defect in Type III hyperlipoproteinemia (broad- disease) may be ineffective removal of chylomicron remnant particles from the arterial wall,11 due to a failure of the liver to recognize such particles.15... 

G.A. Langner, E.h. Birkenmeier, O. Ben-Zeev, M.C. Schotz, H.O. Sweet, M.T. Davisson, and J.L Gordon, The fatty liver dystrophy (fid) mutation. A new mutant mouse with a developmental abnormality in triglyceride metabolism and associated tissue-specific defects in lipoprotein lipase and hepatic lipase activities, J. Biol. Chem., 1989, 264, 7994-8003. 

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