Plasma Lipoprotein Patterns

One point to keep in mind when extrapolating data from an animal model to man concerns differences in the distribution of cholesterol over the various plasma lipoprotein fractions. In healthy humans, most of the serum cholesterol is transported in the LDL fraction, whereas in normo-cholesterolemic rabbits and rats, the HDL fraction is the primary cholesterol transport fraction (Terpstra et al, 1981 Van Raaij et al, 1981). 

Day et al. (1979) found that 80% of serum cholesterol in rats was carried in HDL and only 5-10% in LDL. The typical distribution of cholesterol in the healthy human is in the order of 27-35% in HDL and at least 60% in LDL (Myant, 1981). Sixty to 80% of plasma cholesterol in normocholest-erolemic and hypercholesterolemic gerbils is carried in the HDL fraction (Mercer, 1985). 

In this brief overview, diet-induced alterations in blood lipid profiles in three small animal models used in research on diet and human atherosclerosis have been discussed. When evaluating experimental data, it is essential to be aware of differences in the response of various animal models used for the study of the human disease. These considerations include a thorough characterization of the dietary response of the animal 

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H. Lithell, B. Odlind, I. Selinus, A. Lindberg, B. Lindstrom, and L. Frodin, Is the plasma lipoprotein pattern of importance for treatment with cyclosporine Transplant. Proc. 18 50-51 (1986). 

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). 

Bachorik PS. Electrophoresis in the determination of plasma lipoprotein patterns, ha Lewis L, Opplt JJ, eds. CRC Handbook of electrophoresis, Vol. 11. Bosa Raton CRC Press, 1980 7. 

A4. Agardh, G. D., Nilsson-Ehle, P., and Schersten, B., Improvement of the plasma lipoprotein pattern after institution of insulin treatment in diabetes mellitus. Diabetes Care 5, 322-325 (1982). 

Some of these differences are reflected by the plasma lipoprotein patterns for example, the major plasma lipoprotein fractions in mice, rats, hamsters, rabbits, and dogs are the HDL fractions, whereas in guinea pigs and Old World monkeys the LDL fraction is the dominant fraction (Alexander and Day 1973 Terpstra et al. 1981 Barrie, Nash, and Watson 1993 Terpstra and Beynen 1984 Hollanders et al. 1986 ... 

Richelle M, Rubin M, Kulapongse S, et al. Plasma lipoprotein pattern during long-term home parenteral nutrition with two lipid emulsions. JPEN J Parenter Enteral Nutr 1993 17 432-437. Masclans JR, Iglesia R, Bermejo B, et al. Gas exchange and pulmonary haemodynamic responses to fat emulsions in acute respiratory distress syndrome. Intensive Care Med 1998 24 918-923. 

Familial lipoprotein lipase deficiency is characterized by a massive accumulation of chylomicrons and a corresponding increase in plasma triglycerides or a type I lipoprotein pattern. Presenting manifestations include repeated attacks of pancreatitis and abdominal pain, eruptive cutaneous xanthomatosis, and hepatosplenomegaly beginning in childhood. Symptom severity is proportional to dietary fat intake, and consequently to the elevation of chylomicrons. Accelerated atherosclerosis is not associated with this disease. 

Details of plasma lipoproteins and their metabolism are given in Section 5.5. Most of the cholesterol in the blood is carried as part of low density lipoprotein (LDL) or high density lipoprotein (HDL), whereas most triglyceride, in the fasting state, is carried by very low density lipoprotein (VLDL). The relative concentrations of these lipoproteins constitute the lipid profile and determine CVD risk. Diabetics are more likely to show an unhealthy profile with elevated concentrations of LDL and triglyceride but reduced HDL concentration. This pattern can be partly explained by enhanced fatty acid liberation from adipocytes as a consequence of insulin resistance in that tissue and due to reduced removal from the circulation of triglycerides, which is also insulin dependent. 

Patient Population. The proband of the B family, T.B., was referred to the Lipid Research Clinic at The Johns Hopkins Hospital at the age of five years because of hypercholesterolemia of 900 mg/100 ml. She had multiple planar xanthomas that had first appeared at three years of age. The patient was free of symptoms of ischemic heart disease. The index lipoprotein pattern was type lib (57), with marked hypercholesterolemia, hyperbeta-lipoproteinemia, a mild hyperprebetalipoproteinemia and hypertriglyceridemia. None of the relatives of T.B. had xanthomas or corneal arcus one (J.S.) developed signs of premature coronary atherosclerosis at the age of 43 years. Increased total plasma and LDL cholesterol levels were transmitted over three generations on both maternal and paternal sides of the family (Fig. I). The parents of the proband, S.B. and K.B., had endogenous hypertriglyceridemia as well. Two normolipidemic members of this family (S.B., Jr. and E.B.), were also studied. 

A. Familial lipoprotein lipase deficiency (Type I lipoprotein pattern on electrophoresis). Serum triglycerides become elevated with particular elevation of chylomicrons. Tliere are xanthomas, rather than atherosclerosis. Pancreatitis may result from the action of pancreatic lipase on these elevated chylomicrons, with resultant excess triglyceride breakdown in the pancreas, pancreatic injury, and release of more pancreatic lipase. (Note that the body contains different kinds of lipases. There is a pancreatic lipase, which is a digestive enzyme a lipoprotein lipase, which is an extracellular enzyme that breaks down plasma triglycerides, thereby enabling fatty acids to enter cells and an intracellular lipase that breaks down stored triglycerides). 

Familial Combined Hyperlipidemia About 10% to 15% of patients with premature CHD actually have familial combined hyperlipidemia (FCHL). This disorder is recognized as a distinct phenotype by studying family members of survivors of myocardial infarction. Patients with FCHL can have increased plasma concentrations of total and LDL cholesterol (type Ila), or triglyceride (type IV), or both (type lib). In all cases, apo B-lOO concentrations are increased. The presentation of lipoprotein patterns can vary in an individual with time. Furthermore, patients with hypertriglyceridemia with normal partners tend to have offspring with hypercholesterolemia, and vice versa. 

Diagnosis of the Type III Lipoprotein Pattern. The ratio of VLDL cholesterol to plasma triglyceride, expressed in terms of mass, is 0.2 or lower in normal samples and in those from patients with lipoprotein disorders other than type III hyperlipidemia. In type III hyperlipoproteinemia, the ratio is 0.3 or higher because of the presence of p-VLDL, and the elevated ratio can persist even after treatment. 

In addition, P-VLDL can also be observed directly by subjecting the VLDL fraction to agarose gel electrophoresis, where it migrates electrophoretically with LDL rather than VLDL (see Figure 26-26). The combination of a VLDL cholesterol/plasma triglyceride ratio of 0.3 or higher and the observation of p-VLDL in the ultracentrifugal supernatant establishes the type III lipoprotein pattern. 

A control and two patients with hyperlipidemia are studied after an overnight fast. Their plasma lipoprotein electrophoresis patterns are shown below, the control being in the middle lane. One of the patients has a pattern typical of type I lipoprotein lipase deficiency, and the other of type Ila familial hypercholesterolemia. Which of the bands observed in the electrophoretic gel patterns represents a lipoprotein fraction that is abnormally abundant after fasting and that is most enriched in triacylglycerides ... 

Agarose Gel Electrophoresis Separation Patterns of Plasma Lipoproteins in Three Selected Patients Following a Fast... 

While the LDL pathway for control of cholesterol uptake was elucidated using cultured cells, it also appears to be functional in vivo. The pattern of regulation depicted in Fig. 5 has been confirmed in freshly isolated blood leukocytes and lymphocytes [89-92]. In addition, administration of 4-aminopyrazolepyrimidine, a drug which suppresses lipoprotein release from animal liver [93], elevates HMG-CoA reductase levels and cholesterol synthesis in non-hepatic tissues [94,95]. These observations are consistent with the hypothesis that non-hepatic cells exhibit a low rate of cholesterol synthesis because they utilize cholesterol synthesized by the liver and present in the plasma lipoproteins [96],... 

Bang, H.O., Dyerberg, J., and Nielsen, A. (1971) Plasma Lipid and Lipoprotein Pattern in Greenlandic West-Coast Eskimos, Lancet 1,1143-1146. 

Hyperlipemia (Man and Peters, 1934, 1935) predominantly affecting the triglycerides (Harris et al., 1953 Hirsh et al., 1953) is usually associated with poorly controlled diabetes mellitus. The lipoprotein pattern is characterized by elevation of chylomicrons and VLDL with diminished levels of LDL and HDL (Hamwi et al., 1962). Correlation of the hyperlipemia with the diabetic status is indicated by the return to normal of plasma lipid and lipoprotein upon control of the diabetes (Salt et al., 1960a Lindgren and Nichols, 1960). 

Apart from the hyperlipoproteinaemias that act as determinants of abnormal plasma lipoprotein concentrations, conditions with abnormally low concentrations of certain lipoproteins are also encountered and are generally referred to as the hypolipoproteinaemias. Tangier disease is one such condition that occurs as a rare inherited condition with autosomal recessive characteristics. The condition, a familial HDL deficiency, is characterized by cholesteryl ester accumulation in the reticuloendothelial system, which is similar in pattern to other lipid-storage diseases, such as gangliosidoses. Atheroma are substantially absent from the aorta and coronary vessels of such patients. The plasma cholesterol concentration is reduced and the triacylglycerol concentration is normal or increased in these cases. 

It is now well established that very low density and low density lipoproteins are synthesized in the liver. Data supporting this conclusion have been obtained from studies on plasma triglyceride metabolism, the fatty liver and its origin, and protein biosynthesis in the liver. Many of the studies used animals which have a somewhat different lipoprotein pattern than the human. Metabolic sequences differ in detail between species and unique model systems are required (Farquhar et al. 1965). Nevertheless fundamental aspects of lipoprotein metabolism such as liver synthesis have been confirmed in several animals. 

Once the presence of fasting lipemia has been established, di-ffereyitiation between primary and secondary hyperlipemias can usually be made on the basis of presence or absence of clinical and laboratory findings characteristic of an underlying disease. Plasma lipid and lipoprotein patterns as determined by lipid analyses, ultracentrifugation and electrophoresis are not necessarily diagnostic since similar findings are present in EHL and hyperlipemia of diabetic ketoacidosis, acute pancreatitis, alcoholism, etc. (Schettler 1955, Lees and Fredrickson 1964, Jahnke 1965). 

Bang, H.O., Dyerberg, I Nielsen, A.B. 1971. Lancet, 710, 1143-1145. Plasma hpid and lipoprotein pattern in Greenlandic West-coast Eskimos. 

Plasma lipid and lipoprotein pattern in Greenlandic West Coast Eskimos. 

The classification of hyperUpidaemias is confusing as there are two means of classification - the Fredrickson based on the pattern of plasma lipoproteins in each condition, and the Goldstein based on the underlying enzyme defects. Type I hyperlipidaemia (Fredrickson) is a lipoprotein lipase or apolipoprotein-C2 deficiency. It leads to massive Hpid deposition and presents in childhood. Type Da hyperlipidaemia (familial hypercholesterolaemia) is a severe illness, not to be confused with common hypercholesterolaemia. Familial hypercholesterolaemia presents in childhood with deposits of cholesterol in the skin and ischaemic heart disease in adolescence. 

In some species, like man, guinea pig and pig, lipoproteins of the LDL type, in which apolipoprotein B predominates, account for more than 50% of the total substances of density < 1.21 gml". They are the LDL mammals. In the vast majority of mammals, however, HDL are the predominant class and may account for up to 80% of plasma substances of density < 1.21 g ml. Herbivorous species, with the exception of guinea pigs, camels and rhinos, and carnivores are HDL mammals. It is worth noting that although rats are most frequently the animal of choice for the study of lipid biochemistry in the research laboratory, their lipoprotein pattern is of the HDL type and very different from that of man. Caution needs to be exercised in extrapolating results on experimental animals to the human situation. 

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