Hyperlipemia lipoproteins

Hyperlipemia may manifest itself by an increased concentration of lipids, or certain groups thereof. For example, hypercholesterolemia and hypertriglyceri-demia may be mentioned in this connection. Since practically all the blood plasma lipids make part of lipoproteins, hyperlipemias may be reduced to one of the hyper-lipoproteinemia forms which differ in the varied ratios of plasma lipoproteins of different groups. 

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. 

LI. Lever, W. F., Smith, P. A. J., Hurley, N. A., Effect of intravenous heparin on the plasma lipoproteins in primary hypercholesteremic and idiopathic hyperlipemia. Science 118, 653-654 (1953). 

The extreme hypoalbuminemia of the nephrotic syndrome can be attributed to the sustained urinary loss of albumin (S39), but it is doubtful whether albumin deficiency plays a causal role in the hyperlipemia and hypercholesterolemia found in this condition. Low-density lipoprotein (LDL) (90% lipids) is converted by lipoprotein lipase in vivo to high-density lipoprotein (HDL) (70% lipids), and the liberated fatty acid anions are bound and transported by plasma albumin. In normal nonlipemic serum the mean nonesterifled fatty acid/albumin molar ratio is 0.95 0.04, while in nephrotic sera—lipemic because of accumulation of LDL-triglycerides —the corresponding ratio is about 3 (C4). The plasma hyperlipemia which is observed in the nephrotic syndrome, and can be induced in rats by injections of antikidney serum, has been considered to result from albumin deficiency (R26). However this suggestion is not borne out by more recent studies (R25) and is contradicted by the failure of LDL to accumulate in the blood of analbuminic subjects (03). Plasma lipemia in the nephrotic syndrome apparently is due to loss or inhibition of lipoprotein lipase activity. 

The normal ovarian and adrenal lipid is intracellular, but there is another important situation in which a lipoid mesophase may be present more or less normally, entirely outside cells. This is in the plasma (39), in the low density /3-lipoprotein fraction (Sf 12 to 20). In health, this fraction is low or absent until adult life. It begins to increase in males from about the age of 20 onward in females, it remains low until the menopause, after which it increases rapidly as in males. It can be produced experimentally in rabbits, dogs, fowls, and some other animals by feeding cholesterol. Analogous to this is the pathological increase seen in humans with certain renal and metabolic disorders, especially in diabetes mellitus and in hereditary or essential hyperlipemia, where there is an increase in several fatty components in the blood, with abnormal deposition of fat in various tissues. 

The extensive work on this subject by Macheboeuf and Tayeau (1941a, b) has been reviewed by Gurd (19W). It will be sufScient here to say that compounds containing hydrocarbon chains are able to displace lipids from lipoproteins and that their action is dependent on the nature of the surfactant (ionic, nonionic), length of the hydrocarbon chain, and their critical micellar concentration. A more detailed analysis of the interaction between nonionic surfactants and isolated serum lipoproteins will be given in the section concerning the mechanism of Triton WR-1339 hyperlipemia. 

Possible physiological inhibitors of plasma lipoprotein lipase have been reported in plasma (Hollett and Meng, 1957), platelets (Hollett and Nestel, 1960), and white blood cells (Fekete et al., 1958). Their exact functional role remains to be established. Inhibition of plasma lipoprotein lipase activity has also been reported in pathological conditions, such as experimental pancreatitis (Kessler et al., 1962), clinical pancreatitis (Kessler et al., 1963), and idiopathic hyperlipemia (Klein and Lever, 1957). Several agents have been found to inhibit plasma lipoprotein lipase activity protamine and toluidine blue (Brown, 1952 Bragdon and Havel, 1954), Triton WR-1339 (Schotz et al., 1957), Triton A-20 and Tween 80 (Kellner et al., 1951), pituitary extracts (Rudman and Seid-... 

In 1951 Kellner et al. reported that administration of the nonionic detergents Triton A-20 or Tween 80 to rabbits and guinea pigs was followed by a sustained hyperlipemia. This observation was later extended to other animal species mice (Hirsch and Kellner, 1956a, b), rats (Friedman and Byers, 1953), and dogs (Scanu et al., 1961). Studies by Friedman and Byers (1953, 1957) and Hirsch and Kellner (1956a, b) led to the hypothesis that the hyperlipemia was secondary to the action of the detergent on the physical and chemical properties of plasma lipoproteins. Experimental support for this hypothesis was provided by the... 

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). 

First of all, the typing of hyperlipemias seems to be essential requirement inasmuch as the responses of the Types to diet or drugs are substantially different. Several of the lipoprotein abnormahties appear to lead to vascular disease at an accelerated rate. In Lebanon, for example, there are relatively more cases of hyperlipidemia of Type II. These patients are predominantly children, who have xanthomas in their pre-teen years, angina and typical coronary artery disease in their teens, and an outlook for an average life-expectancy of 25 years [447]. Hyperlipidemia appears to be the primary disease in these children and apparently, leads to the secondary and fatal coronary artery disease. A thorough study of the abnormal lipoproteins of these children is obviously a necessity. 

As techniques become more sophisticated, more attention is being directed toward the lipoproteins. Stein and Steln concluded from their own and other studies that lipoprotein release is regulated by the rate of fatty acid synthesis and esterification. Lees has reported that protein portions of the lipoproteins may be critical in atherogenesis while Slack and Mills indicate that in familial hyperbetalipo-proteinemia an abnormal lipoprotein is present. Several authors have reported that serum globulins may play a role in hyperlipemia in individual patients either by their absence or by complexing with a lipoprotein . Platelets and thrombus formation which undoubtedly play a role in atheromata... 

In pure EFH, plasma triglycerides are normal or only slightly elevated, in accordance with the low triglyceride concentration in beta-lipoproteins. When high triglyceride levels are observed associated with features of EFH rather than of essential hyperlipemia, one is probably dealing with a separate syndrome (see page 460). 

Comparative studies in patients with EFH and essential hyperlipemia, on the effect of CPIB and dextrothyroxine on low and very low density lipoproteins respectively, were performed by Strisower and Strisower (1964). CPIB lowered very low density lipoproteins (and thus triglycerides) more than dextrothyroxine, but the latter drug was superior to CPIB as regards the depressing effect on serum beta-lipoproteins and thus on cholesterol (see also page 434). 

Herbst, F. S. M., W. F. Lever, and N. A. Hurley Idiopathic hyperlipemia and primary hypercholesteremic xanthomatosis. VI. Studies of the serum proteins and lipoproteins by moving boundary electrophoresis and paper electrophoresis before and after administration of heparin. J. invest. Derm. 24, 507 (1955). 

This grouping is possibly not homogenous and may subsequently be subdivided. It includes subjects who have been described as having mixed hyperlipemia by Kuo and Basset (1963), calorie induced hyperlipemia by Kin sell and Schlierf (1965) and probably type V of Fredrickson s and Lees classification (1965). Whatever the homogeneity, it appears that these individuals accumulate very low density lipoproteins in plasma under essentially all dietary conditions except absolutely or relatively low calorie intake, and in some except during the administration of insulin. 

It is likely that cases who have been described in the past as essential hyperlipemia on the basis of lipemic plasma and who exhibited tendon xanthomas belong in this group. Cases of essential hypercholesterolemia with and without plasma turbidity, whose plasma triglycerides exceed the levels expected from increased /3-lipoproteins, would qualify for membership. Such cases can be found in reports by Lever et al. (1954), Adlersberg (1955), Furman et al. (1961), Kuo and Basset (1963) and others. 

An excellent review of the subject is that of Crocker (1951). Xanthomatosis is the most common and in many instances the first readily recognizable sign of severe EHL. Thannhauser (1957) has emphasized the early and quite consistent appearance of xanthomas in children with hyperlipemia, whereas in adults they occur in only about 50% of cases. The same figure was given by Barrie (1957) and a similar incidence one year later by Gadrat (xanthomas in 25 out of 49 patients with EHL). A correlation between the prevailing lipoprotein pattern and the different forms of xanthomas has been attempted by Gofman et al. (1954)... 

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