Donald S. Fredrickson

A specific apoprotein activator for lipoprotein lipase

Abstract These studies were designed to determine which of the apoproteins of high density lipoprotein (HDL) function as the cofactor for lipoprotein lipase (LPL). ApoLP-gln and apoLP-thr, the major HDL apoproteins, as well as apoLP-val, a minor apoprotein constituent, are inactive as cofactors even in the presence of phospholipid. ApoLP-ala, another minor constituent, is inactive alone but in the presence of phospholipid stimulates lipase activity twofold. Only apoLP-glu is able to stimulate LPL activity in the absence of phospholipid and, in the presence of phospholipid, increases activity twelvefold over baseline levels. It is possible that apoLP-glu and perhaps apoLP-ala are obligatory “co-factors” for the hydrolytic step required for normal clearing of triglyceride from the plasma.

Coronary Artery Disease in 116 Kindred with Familial Type II Hyperlipoproteinemia

Analysis of cardiovascular status in adult relatives of 116 kindred affected with familial hyperbetalipoproteinemia (type II hyperlipoproteinemia) was carried out to assess coronary artery disease (CAD) risk in relatives with type II (II) compared to unaffected family members. Over 90% of the 738 living relatives were interviewed by one investigator and 12 lead electrocardiograms were obtained. In these, and in 285 deceased relatives, physician and hospital records were utilized to determine CAD events by standard criteria. This study, the largest of its kind, permitted more precise and extensive determination of the CAD risk accompanying severe hyperbetalipoproteinemia than has heretofore been possible. CAD was diagnosed in 29.5% of IIs compared with 10.5% of normal relatives (N) (P < .001). The IIs and Ns did not differ significantly with regard to age distribution, sex, hypertension, smoking habits, or body mass index. According to the Rose questionnaire, angina pectoris was diagnosed in 21.8% of IIs and 6.5% of Ns (P < .001). Documented myocardial infarction occurred in 6% of IIs versus 1% of Ns (P = .002). CAD death or myocardial infarction occurred in 10.1% of IIs compared with 1.8% of Ns (P < .001). The cumulative probability of nonfatal or fatal CAD by age 40 in male IIs was 16% (1 in 6); by age 60, the expectation of an event had risen to 52% (1 in 2). Among male Ns, the risk of nonfatal or fatal CAD by age 60 was 12.7%, lagging 20 years behind that seen in male IIs. In female IIs, the risk of nonfatal or fatal CAD by age 60 was 32.8% compared with only 9.1% in female Ns.

Editorial A System for Phenotyping Hyperlipoproteinemia

IT HAS been well established that the lipids in plasma do not circulate free but combine in orderly arrangements with protein. Most of the lipid is combined with two major proteins, the a and ,3 polypeptides, to form lipoproteins that extend over a wide density range, from greater than 1.21 to that of fat itself, about 0.9 Gm. per ml. Changes in this lipoprotein spectrum occur in many diseases. In many instances the lipoprotein abnormality appears to be the primary expression of a biochemical defect. These disorders are usually familial, relatively common, and of particular interest in relation to atherogenesis and coronary heart disease. Despite their relative importance, the present understanding of these hereditary defects is meager and their classification chaotic. For the determination and study of such abnormalities a number of methods have been available for some time. The minimum is a determination of plasma cholesterol and glyceride content. The maximum in resolving power is offered by the ultracentrifuge, which is capable of measuring changes within small increments of the density spectrum. When one is concerned particularly with familial hyperlipoproteinemia, necessitating screening of large kindreds, neither of these approaches has proved ideal. Measurement of triglyc-

The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice

Identification of mutations in the ABCA1 transporter (ABCA1) as the genetic defect in Tangier disease has generated interest in modulating atherogenic risk by enhancing ABCA1 gene expression. To investigate the role of ABCA1 in atherogenesis, we analyzed diet-induced atherosclerosis in transgenic mice overexpressing human ABCA1 (hABCA1-Tg) and spontaneous lesion formation in hABCA1-Tg × apoE-knockout (KO) mice. Overexpression of hABCA1 in C57BL/6 mice resulted in a unique anti-atherogenic profile characterized by decreased plasma cholesterol (63%), cholesteryl ester (63%), free cholesterol (67%), non-high density lipoprotein (HDL)-cholesterol (53%), and apolipoprotein (apo) B (64%) but markedly increased HDL-cholesterol (2.8-fold), apoA-I (2.2-fold), and apoE (2.8-fold) levels. These beneficial changes in the lipid profile led to significantly lower (65%) aortic atherosclerosis in hABCA1-Tg mice. In marked contrast, ABCA1 overexpression had a minimal effect on the plasma lipid profile of apoE-KO mice and resulted in a 2- to 2.6-fold increase in aortic lesion area. These combined results indicate that overexpression of ABCA1 in C57BL/6 mice on a high cholesterol diet results in an atheroprotective lipoprotein profile and decreased atherosclerosis, and thus provide previously undocumented in vivo evidence of an anti-atherogenic role for the ABCA1 transporter. In contrast, overexpression of ABCA1 in an apoE-KO background led to increased atherosclerosis, further substantiating the important role of apoE in macrophage cholesterol metabolism and atherogenesis. In summary, these results establish that, in the presence of apoE, overexpression of ABCA1 modulates HDL as well as apoB-containing lipoprotein metabolism and reduces atherosclerosis in vivo, and indicate that pharmacological agents that will increase ABCA1 expression may reduce atherogenic risk in humans.

β-Sitosterolemia and Xanthomatosis

Recently, Bhattacharyya and Connor described in two sisters a lipid-storage disease, β-sitosterolemia and xanthomatosis,1 with tendon and tuberous xanthomas appearing at an early age despite normal...

Dietary and Drug Treatment of Primary Hyperlipoproteinemia

Abstract The first step in the management of primary hyperlipidemia is its translation into hyperlipoproteinemia, which can be done by measuring the plasma cholesterol and triglyceride concentratio...

Further Observations on the Activation and Inhibition of Lipoprotein Lipase by Apolipoproteins

ApoC-II was the only apolipoprotein from human very low density lipoprotein that activated rat adipose tissue lipoprotein lipase. Activation was blocked by antiserum against apoC-II. Addition of increasing amounts of activator did not alter the apparent Km of lipoprotein lipase (0.32 mM triolein), but it did produce a progressive increase in the apparent Vmax from 0.8 to 2.2 μmoles free fatty acid/mg hour−1. Substrate concentrations above 1.27 mM triolein diminished activation by 0.25–5.0 μg/ml of apoC-II as much as 20%. Reversal of this apparent substrate inhibition was achieved by increasing the activator concentration to 50.0 μg/ml. Each of five nonactivating apolipoproteins-apoC-I, C-III-1, C-III-2, A-I, and A-II-inhibited lipoprotein lipase up to 85–100%. ApoC-II also produced less inhibition under appropriate conditions. Inhibition was dependent on apoprotein concentration, inversely related to substrate triglyceride concentration, and unobserved with nonlipoprotein proteins. The inhibitory capacity of the nonactivating apolipoproteins was about the same, was independent of apoC-II concentration, and occurred when the ratio of nonactivator apoprotein to triglyceride exceeded 3% (w/w). It is possible that these apoproteins function partly to modulate the hydrolysis of very low density lipoprotein triglyceride by lipoprotein lipase.

THE METABOLISM OF CHYLOMICRA. I. THE REMOVAL OF PALMITIC ACID-1-C14 LABELED CHYLOMICRA FROM DOG PLASMA

It is now generally accepted that the intestinal lymphatics constitute the exclusive pathway for the absorption of long chain fatty acids, whether ingested unesterified or as glycerides. These fatty acids appear in the thoracic duct lymph as chylomicra. The subsequent fate of the absorbed fat has been explored very little, and the role of plasma lipoproteins in chylomicron transport and the sites of removal of the absorbed fat remain unknown. Approximately 95 per cent of long chain fatty acids appear in the lymph as triglycerides and 5 per cent as phospholipids (1). Bergstrom, Borgstrom, and Rottenberg (2) fed labeled stearic acid and tristearin to fasting rats. Over a period of 3 to 4 hours, approximately 1 mg. per minute of fatty acids was delivered to and removed from the total plasma, which contained only about 5 mg. of preformed triglycerides. The maximum specific activities of plasma triglyceride fatty acids were only 4 and 15 per cent of the specific activities of the fed stearic acid and tristearin, respectively. The authors suggested that the absorbed triglycerides were not mixing appreciably with the existing plasma triglycerides. Their data did not exclude the possibility that the plasma triglycerides were exchanging rapidly with a large triglyceride pool.

Immunoreactive Insulin, Glucose Tolerance, and Carbohydrate Inducibility in Types II, III, IV, and V Hyperlipoproteinemia

The elevation of plasma glycerides by a high carbohydrate diet (carbohydrate induction) has been systematically correlated with glucose tolerance, insulin output and ponderal index in normals and in patients with different types of hyperlipoproteinemia. Carbohydrate inducibility (ΔTG) was similar in normals and patients with Type II hyperlipoproteinemia. Delta TG was nearly always much greater than normal in Type III, and was quite heterogeneous in type IV. The scatter in ΔTG values in Type V patients was extremely great. The basal triglyceride and ΔTG were positively correlated only in Type IV. Abnormal glucose tolerance was present in approximately one third of Types II and III, one half of Type IV and 80 per cent of Type V patients. Hyperinsulinemia was present in most Type V patients, while a majority of Type II and III patients had relatively normal insulin levels. Approximately one third each of the Type IV patients had low, normal, and abnormally high insulin levels. Increasing insulin and insulinogenic indices were correlated with increased ATG in the normal, but not in any of the patient groups. In the specific groups of hyperglyceridemic patients in this study, plasma insulin levels did not appear to be a primary determinant of the degree of carbohydrate induction.

Enzyme deficiency in cholesteryl ester storage disease

Cholesteryl ester storage disease has been shown to involve severe deficiency of acid cholesteryl ester hydrolase and triglyceride lipase activity in liver, spleen, and lymph node. The cholesteryl ester hydrolase was also deficient in aorta. Tissue storage of both cholesteryl esters and triglycerides is generalized. Both the lipid and enzymatic changes are very similar to those in Wolmans disease.