Disorders of lipoprotein metabolism

Disorders of lipoprotein metabolism involve perturbations which cause elevation of triglycerides and/or cholesterol, reduction of HDL-C, or alteration of properties of lipoproteins, such as their size or composition. These perturbations can be genetic (primary) or occur as a result of other diseases, conditions, or drugs (secondary). Some of the most important secondary disorders include hypothyroidism, diabetes mellitus, renal disease, and alcohol use. Hypothyroidism causes elevated LDL-C levels due primarily to downregulation of the LDL receptor. Insulin-resistance and type 2 diabetes mellitus result in impaired capacity to catabolize chylomicrons and VLDL, as well as excess hepatic triglyceride and VLDL production. Chronic kidney disease, including but not limited to end-stage... 

Patients with abetalipoproteinaemia, a rare inborn disorder of lipoprotein metabolism, are totally deficient in vitamin E fiom birth and, if untreated, invariably develop a characteristic pigmentary retinopathy similar to that seen in retinitis pigmentosa and peroxisomal disorders. The same retinopathy has been observed in other patients with severe and chronic vitamin E deficiency. A essive vitamin E replacement therapy in all these patients has been shown either to prevent, to halt the progression of, or in some cases, to improve the characteristic visual abnormalities (Muller and Lloyd, 1982). 

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). 

Reichl D, Miller NE. Pathophysiology of reverse cholesterol transport. Insights from inherited disorders of lipoprotein metabolism. Arteriosclerosis. 1989, 9 785-797. 

Rader DJ, Hobbs HH Disorders of lipoprotein metabolism, in Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL (eds) Harrison s Principles of Internal Medicine. 16th ed. McGraw-Hill, New York, 2005, pp. 2286-98. 

Three disorders of lipoprotein metabolism share these characteristics familial hypobetal-ipoproteinemia, chylomicron retention disease, and ABL (Table 27-2). The presence or absence of specific plasma apoB lipoproteins, as well as their mode of inheritance, can be useful when attempting to differentiate between these disorders. Symptoms associated with familial hypo-betalipoproteinemia are usually milder than for the other two and are inherited as dominant traits, that is, symptoms are observed in at least one parent of an affected offspring. Chylomicron retention disease is an autosomal recessive disorder with a severe phenotype commonly presenting soon after birth. Plasma lipoprotein analysis from affected individuals shows a specific absence of chylomicrons (apoB48) but normal amounts of VLDL and LDL (apoB 100). In our patient, evidence of recessive inheritance and absence of all apoB-containing lipoproteins implicates ABL as the most likely diagnosis. 

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. 

The first patient described by Kelley et.al.(l) also had an abnormal lipoprotein pattern consistent with Type II hyperlipo-proteinaemia. No other family member even those with reduced APRTase deficiency had Type II hyperlipoproteinaemia. In the present family the serum cholesterol serum triglycerides and lipoprotein pattern were determined and were normal for the propositus and her mother. However her father who had normal APRTase activity had an elevated concentration of serum triglycerides and showed a raised pre-3 band both characteristic of T3 e IV hyperlipoproteinaemia. There is thus no essential association between APRTase deficiency and a disorder of lipoprotein metabolism, since they occur independently in the present kindred. 

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... 

Disorders in lipoprotein metabolism are critical in the etiology of several disease states, such as coronary heart disease and atherosclerosis. Thus, there is considerable interest in the development of novel methods for the analysis of lipoprotein complexes. A simple chromatographic method for the separation of high-density lipoprotein (HDL), low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) from intact serum or plasma has been reported recently [65]. The separation was achieved by using an hydroxyapatite column and elution with pH 7.4 phosphate buffer with lOOpl injections of whole... 

Sohar, E., Bossak, F., Adlersberg, D., Correlative studies of serum proteins lipoproteins and glycoproteins in inborn disorders of lipid metabolism. J. Lab. Clin. Med. 5, 716 (1957). 

In this article we shall review recent advances in plasma lipoproteins, apolipoproteins, and those proteins concerned with lipoprotein lipid metabolism. This is a rapidly growing field, far too large to enable all aspects to be covered in a single paper. In order to keep to a manageable size, we shall focus on areas in which there have been recent major advances. Our treatment of other areas will be brief, as adequate reviews are in most cases available. Clinical details of primary disorders of plasma lipid metabolism are very well covered in a series of reviews in The Metabolic Basis of Inherited Disease (5th Ed., J. B. Stanbury, J. B. Wyngaarden, D. S. Fredrickson, J. L. Goldstein, and M. S. Brown, eds.) (B52, G13, G20, H24, N8, S3, S56). Disordered lipid metabolism, and especially secondary disorders of lipid metabolism, are equally well covered in Metabolic Control and Disease (8th Ed., P. K. Bondy and L. E. Rosenberg, eds.) (H16). 

A disorder of lipid metabolism, in which absence of lipoprotein lipase activity due to an absolute apoC-II deficiency results in marked hypertriglyceridemia (Type I phenotype), has been reviewed elsewhere (N8). There are some unexplained differences in the clinical picture and plasma lipoprotein pattern between apoC-II deficiency and primary lipoprotein lipase deficiency. In apoC-II deficiency, symptoms appear to be milder (but recurrent abdominal pain, caused apparently by acute pancreatitis, is a frequently reported symptom). Patients do not show xanthomas or hepatomegaly, and few have splenomegaly (all features of lipoprotein lipase deficiency). Diagnosis is by electrophoresis of the C apolipoproteins, and a plasma triglyceride concentration usually 1000-3000 mg/dl (N8). There may be an increase in plasma VLDL concentration, whereas in classical lipoprotein lipase deficiency plasma VLDL concentration is nearly normal (N8). 

Lipoprotein lipase (EC 3.1.1.34) is an enzyme or group of enzymes which catalyze the hydrolysis of the 1(3) ester bond(s) of triacylglycerols and the 1 ester bond of phospholipids. The enzyme plays a central role in lipoprotein metabolism, being responsible in particular for the hydrolysis of chylomicron and VLDL triglycerides and the formation of remnant particles from these lipoproteins. There have been reviews of this enzyme [e.g., (N9, Ql)] and lipoprotein lipase will not be discussed in detail in this review. Familial lipoprotein lipase deficiency and related disorders of chylomicron metabolism have also been reviewed (B58, N8) and will not be discussed in detail. 

N8. Nikkila, E. A., Familial lipoprotein lipase deficiency and related disorders of chylomicron metabolism. In The Metabolic Basis of Inherited Disease 0. B. Stanbury, J. B. Wyngaarden, D. S. Fredrickson, J. L. Goldstein, and M. S. Brown, eds.), 5th Ed., pp. 622-642. McGraw-Hill, New York, 1983. 

Disorders of lipid metabolism are manifest by elevation of the plasma concentrations of the various lipid and lipoprotein fractions (total and LDL cholesterol, VLDL, triglycerides, chylomicrons) and they result, predominantly, in cardiovascular disease. 

The fact that a number of different abnormal lipoprotein profiles were found in Cora Nari and her siblings, and that each had evidence of coronary artery disease, suggests that Cora has familial combined hyperlipidemia (FCH). This diagnostic impression is further supported by the finding that Cora s profile of lipid abnormalities appeared to change somewhat from one determination to the next, a characteristic of FCH. This hereditary disorder of lipid metabolism is believed to be quite common, with an estimated prevalence of about 1 per 100 population. 

Resveratrol possesses numerous important bioactivities including antiinflammatory, antioxidant, anti-aggregatory functions, and modulation of lipoprotein metabolism [14]. It has also been shown to possess chemopreventive properties against certain forms of cancer and cardiovascular disorders [15]. Subsequent work has shown that resveratrol extends the life spans of lower eukaryotes [16-18]. In mice, long-term administration of resveratrol-induced gene expression patterns that resembled those induced by calorie restriction... 

In addition to commonly determined lipids, the behaviour of plasma carotenoids has been studied by several authors. As early as 1929, Stannus reported an increase of carotenoids in the blood of patients with xanthosis of the skin. More recently, studies by Zollner (1962 b) revealed increases in carotenoids paralleling those in plasma cholesterol. Since carotenoids are of dietary origin, their elevation must be secondary to changes of other lipids or lipoproteins (beta-lipoproteins in particular) which illustrates the difficulties in deciding which changes found in EFH and other disorders of lipid metabolism represent an associated rather than a basic change. Finally, the studies of Pelkonen (1963) should be referred to, in which he reported on the meta holism of vitamin A and D in normal and hyper-cholesterolemic subjects, and on the distribution of these vitamins in the lipoprotein fractions. 

EFH is an hereditary disorder of lipid metabolism. There is always hypercholesterolemia, hyperphospholipidemia and an elevated cholesterol to phospholipid ratio. Characteristic changes in lipoproteins consist of an increased concentration of beta-lipoproteins. One-third to one-half of all patients exhibit skin and/ or tendon xanthomas. 

ANIMALS TRANSPORT LIPIDS in an aqueous environment at concentrations up to one million times their solubility in water. They accomplish this task by surrounding water-insoluble lipids with amphipathic lipids and proteins to form plasma lipoproteins. A major part of lipid transport is to supply energy for muscle contraction and to deliver lipids to adipose tissue for storage. Disorders in lipoprotein metabolism are a major risk factor for premature coronary heart disease throughout the world. These disorders arise from dysfunction in apolipoproteins, particular enzymes, and lipid transfer proteins, and also secondary to disorders in carbohydrate metabolism. 

Plasma lipids are transported in complexes called lipoproteins. Metabolic disorders that involve elevations in any lipoprotein species are termed hyperlipoproteinemias or hyperlipidemias. Hyperlipemia denotes increased levels of triglycerides. 

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