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Survivors of childhood acute lymphoblastic leukemia (ALL) have an increased risk of cardiovascular disease. Small density lipoproteins are atherogenic but have not been studied in this population. We conducted a cross-sectional analysis of 110 ALL survivors (mean age, 24.3 years) to determine prevalence of small dense LDL (pattern B) phenotype in ALL survivors and identify associated factors. Lipid subfractions were measured using Vertical Auto Profile-II. Participants with greater than 50% of LDL-cholesterol (LDL-c) in small dense LDL fractions (LDL(3+4)) were classified as LDL pattern B. Visceral and subcutaneous adipose tissue (VAT, SAT) volumes were also measured by computed tomography. While the mean LDL-c level of ALL survivors was 108.7 ± 26.8 mg/dl, 36% (40/110) of survivors had atherogenic LDL pattern B. This pattern was more common in males (26/47; 55%) than in females (14/63; 22%, P = 0.001) and more common in survivors treated with cranial radiotherapy (15/33; 45%) than in those who were treated with chemotherapy alone (25/77; 33%; P = 0.04, adjusted for age, gender, history of hypertension, and smoking history). VAT was associated with atherogenic lipids: LDL pattern B and LDL(3+4) levels. This association was independent of other measures of body fat. We conclude that a substantial proportion of ALL survivors had an atherogenic LDL phenotype despite normal mean LDL-c levels. An atherogenic LDL phenotype may contribute to the increase in cardiovascular mortality and morbidity in this population.

Low levels of high density lipoprotein cholesterol (HDL-C) are associated with increased risk of coronary heart disease and, in the United States, are often associated with hypertriglyceridemia and obesity. In Turkey, low HDL-C levels are highly prevalent, 53% of men and 26% of women having HDL-C levels 50th percentile for men and women in the United States were excluded from the analysis. As no dietary or behavioral factors have been identified in the Turkish population that account for increased hepatic triglyceride lipase activity, the elevation most likely has a genetic basis. —Bersot, T. P., G. L. Vega, S. M. Grundy, K. E. Palaoğlu, P. Atagündüz, S. Özbayrakçi, O. Gökdemir, and R. W. Mahley. Elevated hepatic lipase activity and low levels of high density lipoprotein in a normotriglyceridemic, nonobese Turkish population. J. Lipid Res.40: 432–438.

Several studies have reported an inverse relationship between hepatic lipase activity and plasma high density lipoprotein (HDL) cholesterol concentrations. The purpose of the present study was to determine whether genetic and pharmacological variation in hepatic lipase activity alters the distribution of HDL subclasses. Two independent analytical methods (nuclear magnetic resonance and gradient gel electrophoresis) were used to compare HDL subclass distributions in 11 homozygotes for the −514C allele of hepatic lipase and in 6 homozygotes for the −514T allele. Mean hepatic lipase activity was 45 ± 15 mmol·l−1·hr−1 in −514C homozygotes and 20 ± 7 mmol·l−1·hr−1 in −514T homozygotes. Both analytical methods indicated that HDL2b was significantly higher and HDL3a was significantly lower in −514T homozygotes than in −514C homozygotes. No differences were noted in the other HDL fractions (HDL2a, HDL3b, and HDL3c). To determine the effects of increased hepatic lipase activity, 20 men were given the synthetic anabolic steroid, stanozolol. Stanozolol treatment increased hepatic lipase activity more than two-fold (38 ± 18 to 85 ± 25 mmol·l−1·hr−1), and markedly reduced the plasma concentrations of the larger HDL subclasses (HDL2b and HDL2a). The plasma concentrations of the smallest HDL subclasses (HDL3b and HDL3c) were unchanged by stanozolol treatment. Taken together, these genetic and pharmacological data indicate that variation in hepatic lipase activity has highly specific effects on the distribution of HDL subclasses in the circulation.—Grundy, S. M., G. L. Vega, J. D. Otvos, D. L. Rainwater, and J. C. Cohen. Hepatic lipase activity influences high density lipoprotein subclass distribution in normotriglyceridemic men: genetic and pharmacological evidence. J. Lipid Res. 1999. 40: 229–234.

We have shown previously that a hepatic lipase allele (designated 2 514T) is common among African Americans and contributes to low hepatic lipase activity in this population. To identify other hepatic lipase alleles as- sociated with low hepatic lipase activity in this population, the coding region and intron-exon boundaries of the he- patic lipase gene were sequenced in 20 African American men with low hepatic lipase activity. Two polymorphisms (N193S and L334F) were associated with low post-heparin plasma hepatic lipase activity and were much more com- mon in African Americans than in whites. This fi nding, together with our previous data on the 2 514T allele, in- dicates that at least three different hepatic lipase polymor- phisms associated with low hepatic lipase activity are com- mon among African Americans. Analysis of hepatic lipase haplotypes revealed that 97% of African Americans have at least one hepatic lipase allele that is associated with low he- patic lipase activity.— Nie, L., S. Niu, G. L. Vega, L. T. Clark, A. Tang, S. M. Grundy, and J. C. Cohen. Three polymor- phisms associated with low hepatic lipase activity are com- mon in African Americans. J. Lipid Res. 1998. 39: 1900- 1903.

The –514T allele of hepatic lipase is associated with increased high density lipoprotein-cholesterol levels in men, but not in women. This observation suggests that the –514C to T polymorphism may diminish the response of hepatic lipase to androgens. To test this hypothesis, five –514T and five –514C homozygous men were treated with the anabolic steroid stanozolol for 6 days. The mean increase in hepatic lipase activity was similar in the two groups (45 ± 10 vs. 51 ± 10 mmol·hr-1·l-1, P = 0.5). To evaluate the association between the –514 polymorphism and hepatic lipase activity at different physiological androgen concentrations, hepatic lipase genotypes and activities were measured in 44 men and 40 premenopausal women. The effect of the –514T allele on hepatic lipase activity was significant and quantitatively similar in both sexes. These data indicate that the –514 polymorphism does not influence the response of hepatic lipase activity to androgens, and that the effects of this polymorphism on hepatic lipase activity are independent of androgen action.—Vega, G. L., J. Gao, T. P. Bersot, R. W. Mahley, R. Verstraete, S. M. Grundy, A. White, and J. C. Cohen. The –514 polymorphism in the hepatic lipase gene (LIPC) does not influence androgen-mediated stimulation of hepatic lipase activity. J. Lipid Res. 1998. 39: 1520–1524.

The -514 polymorphism in the hepatic lipase gene (LIPC) is associated with decreased hepatic lipase activity. In the present study, the interaction between body mass index (BMI), the -514 polymorphism, and hepatic lipase activity was examined in 118 white men and in 51 African American men. BMI was significantly positively correlated with hepatic lipase activity in both populations. BMI was similar in men with genetic differences in hepatic lipase activity, indicating that high hepatic lipase activity did not cause increased BMI. The data therefore suggest that high BMI leads to increased hepatic lipase activity. The actions of BMI and the -514 polymorphism on hepatic lipase activity appear to be additive and independent, rather than synergistic. This finding indicates that hepatic lipase activity is a multifactorial trait, determined in part by polymorphism within the LIPC gene as well as by factors that influence BMI.—Nie, L., J. Wang, L. T. Clark, A. Tang, G. L. Vega, S. M. Grundy, and J. C. Cohen. Body mass index and hepatic lipase gene (LIPC) polymorphism jointly influence postheparin plasma hepatic lipase activity. J. Lipid Res. 1998. 39: 1127–1130.

Low plasma concentrations of high density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apoA-I) are major risk factors for coronary heart disease (CHD). Low HDL levels are common in patients with hypertriglyceridemia, but they also occur in those with normal plasma lipids; the latter include obese patients and cigarette smokers, though other patients with low HDL levels are neither obese nor smokers. The present study was designed to define metabolic causes of low apoA-I levels in normal-weight, normolipidemic patients. ApoA-I tracer studies were carried out in two groups of normolipidemic patients having low HDL levels to determine input rates and residence times for ApoA-I; these patients included 11 nonobese nonsmokers and 11 nonobese cigarette smokers. Their results were compared to those of 20 normal-weight, normolipidemic controls with normal HDL levels and 12 obese nonsmokers also having low HDL. In all three groups manifesting low HDL-cholesterol and low apoA-I levels, residence times for plasma apoA-I were reduced by approximately 30%, compared to control subjects with normal HDL levels. In contrast, average input rates for apoA-I were similar among the three low-HDL patients and control subjects. No differences in apoA-I kinetics were observed among any of the three groups with low apoA-I concentrations. Within each of the four groups of the study, however, input rates for apoA-I were highly correlated with plasma concentrations of apoA-I. Thus, for individuals with normal levels of plasma lipids, both residence times and input rates for apoA-I appeared to be important determinants of apoA-I levels. Residence times for apoA-I were reduced in almost all patients with low apoA-I levels, regardless of concomitant factors, whereas input rates were highly variable among individuals.

Familial hypobetalipoproteinemia, a syndrome associated with low plasma cholesterol levels, can be caused by apoB gene mutations. We identified a healthy 42-year-old man whose total plasma cholesterol level was 80 mg/dl. His plasma very low density lipoprotein (VLDL) contained a unique truncated apoB species, apoB-83, in addition to the normal B apolipoproteins, apoB-100 and apoB-48. Virtually no apoB-83 was detectable in his low density lipoprotein (LDL). From the subject's kindred, we identified nine other hypocholesterolemic subjects whose VLDL contained apoB-83. A tendency for cholelithiasis was noted in the apoB-83 heterozygotes, particularly in the older individuals. From the apparent size of apoB-83 on SDS-polyacrylamide gels and its reactivity with apoB-specific monoclonal antibodies, we estimated that it would contain approximately 3700-3800 amino acids. DNA sequencing of apoB genomic clones from two affected individuals revealed that apoB-83 was caused by a C----A transversion in exon 26 of the apoB gene (apoB cDNA nucleotide 11458). This mutation converts Ser-3750 (TCA) into a premature stop codon (TAA) and creates a unique MseI restriction endonuclease site. Thus, a single nucleotide transversion in the apoB gene results in a unique truncated apoB species, apoB-83, and the clinical syndrome of familial hypobetalipoproteinemia.

Familial defective apolipoprotein B-100 is a genetic disorder of apolipoprotein B-100 that causes moderate to severe hypercholesterolemia. A single amino acid mutation in apolipoprotein B diminishes the ability of low density lipoproteins to bind to the low density lipoprotein receptor. Low density lipoproteins accumulate in the plasma because their efficient receptor-mediated catabolism is disrupted. This mutation has been identified in the United States, Canada, and Europe and is estimated to occur at a frequency of approximately 1/500 in these populations. Thus, it appears that this newly described disorder may be a significant genetic cause of hypercholesterolemia in Western societies.

Apolipoprotein A-I (apoA-I) participates in transport of plasma cholesterol. Concentrations of apoA-I depend on the balance between production and fractional clearance. To elucidate factors influencing apoA-I levels, accurate estimates of apoA-I turnover rates may be valuable. We describe a method for isolation of autologous apoA-I and its use in turnover studies. Free apoA-I was isolated from high density lipoproteins (HDL) by treatment with guanidine hydrochloride. This free apoA-I was radioiodinated with 131I and injected into eleven subjects simultaneously with HDL labeled with 125I. Plasma die-away curves of free apoA-I (131I) and HDL apoA-I (125I) were compared; fractional clearance rates averaged 0.256 +/- 0.019 (SEM) and 0.254 +/- 0.017 pools/day, respectively. Although slight differences between the two die-away curves were noted for some of the patients, the differences were relatively small; for the group as a whole, average fractional catabolic rates were not significantly different. Thus, by isolation of autologous apoA-I under the conditions described, free apoA-I seemingly provides a valid method for estimating apoA-I turnover.

This study was carried out to determine whether patients with coronary heart disease (CHD) have an unusually high level of apolipoprotein B (apoB) relative to cholesterol (C) in low density lipoproteins (LDL). Seven groups of men were studied. Seventy-two with normolipidemia (NLP) had CHD documented on clinical grounds; another 34 NLP patients had proven coronary artery disease (CAD) by angiography (greater than 50% occlusion of two or three coronary arteries). Another group of 37 with documented CHD had hypertriglyceridemia (HTG), and still another 25 with HTG had proven CAD. Three normolipidemic control groups consisted of 30 healthy young men, 40 healthy middle-aged men, and 35 hypertensive men. In normolipidemic CHD and CAD patients, plasma LDL-C averaged 142 +/- 37 (SD) and 136 +/- 32 mg/dl, respectively; in HTG patients with CHD and CAD, LDL-C levels were 137 +/- 37 and 127 +/- 34 mg/dl, respectively. These values were near those of hypertensive controls (141 +/- 31 mg/dl), but higher than middle-aged and younger healthy controls (118 +/- 32 and 106 +/- 26 mg/dl, respectively). Levels of LDL-apoB followed a similar pattern: CHD-NLP (88 +/- 25 mg/dl), CAD-NLP (83 +/- 25 mg/dl), CHD-HTG (94 +/- 30 mg/dl), CAD-HTG (89 +/- 25 mg/dl), hypertensive controls (89 +/- 24 mg/dl), middle-aged controls (80 +/- 25 mg/dl) and younger controls (58 +/- 14 mg/dl). Normolipidemic patients with CHD and CAD did not have higher LDL-C and LDL-apoB levels than hypertensive and normotensive controls. HTG patients with CHD and CAD however tended to have higher LDL-apoB levels, and their LDL-apoB/C ratios were higher on average than normal. Nevertheless, among all coronary groups, there were no sizable subgroups with elevated LDL-apoB; only about 11% of all coronary patients had LDL-apoB levels over 120 mg/dl (compared to 8% for normo- and hypertensive controls of middle age). The data of this study therefore suggest that LDL-apoB may not prove to be a better indicator of coronary risk in normolipidemic people, but LDL-apoB could be a superior predictor of risk in HTG patients.

Mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, was used for treatment of 12 patients with moderate hypercholesterolemia, but not classical familial hypercholesterolemia. For most patients, measurements of turnover of low density lipoprotein-apolipoprotein B (LDL-apoB) were made on placebo and during treatment with two doses of mevinolin. LDL turnover was determined after injection of autologous 125I-labeled radioiodinated LDL. Compared to placebo, a low dose of mevinolin (10 mg, twice daily (BID] caused reductions of plasma total cholesterol and LDL-cholesterol averaging 15% and 20%, respectively; corresponding reductions on high doses of mevinolin (20 mg BID) were 22% and 31%, respectively. Triglyceride levels were unchanged by the drug. High density lipoprotein cholesterol levels rose significantly on the high dose, but not on the low dose. Neither dose produced a stastistically significant change in fractional catabolic rate (FCR) for LDL-apoB for the whole group, although several patients had increases in FCR on both doses. In contrast, both doses of mevinolin caused decreases in production rates of LDL-apoB. Thus, the fall in LDL levels in patients with moderate hypercholesterolemia can be explained more by a reduction in the input rate of LDL-apoB than by enhanced fractional removal of LDL from the circulation.

The mechanisms of the hypocholesterolemic effect of polyunsaturated fats (PUSF) are not well understood. One possibility is that these fats uniquely reduce the cholesterol content of lipoproteins. The present study was carried out to determine specifically whether the ratio of cholesterol-to-protein (or apoB) in LDL (or other lipoproteins) is reduced by PUSF; also, lipoprotein composition was examined for other possible changes. Eight men and two women with different levels of plasma cholesterol were studied on the metabolic ward for 8 weeks. They were given a diet high in saturated fats (SF) for 4 weeks and another rich in PUSF for 4 weeks. On PUSF diets, mean plasma cholesterol decreased by 25% (SF = 296 +/- 27 (SEM) vs. PUSF = 223 +/- 21 mg/dl) as did total plasma apoB (155 +/- 8 vs. 116 +/- 13 mg/dl). LDL-Cholesterol decreased by 26%, and LDL-apoB fell by 29%. The mean ratio of cholesterol-to-apoB did not change significantly (SF = 1.52 +/- 0.04 vs. PUSF = 1.48 +/- 0.07). Likewise, HDL-cholesterol decreased by 15% (SF = 51 +/- 5 vs. PUSF = 43 +/- 4 mg/dl), and total plasma apoA-I was reduced by 19% (95 +/- 15 vs. 77 +/- 6 mg/dl); also, no change in the cholesterol-to-apoA-I in HDL was noted. Finally, there were no changes in cholesterol/apoB or triglyceride/apoB ratios in VLDL despite a 23% decrease in plasma triglycerides on PUSF. Thus, the hypocholesterolemic effect of PUSF was uniform for all lipoproteins and usually was accompanied by a corresponding decrease in concentrations of apoprotein constituents.

The turnover rates of low density lipoprotein-apolipoprotein B (LDL-apoB) were determined in 32 men with coronary heart disease (CHD) and 11 control men with normal plasma lipids. Thirty patients with CHD had normal levels of LDL-cholesterol (LDL-C); of these patients, 9 had hypertriglyceridemia and 21 had normal plasma lipids. Mean concentrations of total cholesterol and LDL-C were similar among the control subjects and CHD patients, although the latter had significantly lower HDL-C. In control subjects, transport rates and fractional catabolic rates (FCR) of LDL-B were 10.6 +/- 0.5 (SEM) mg/kg-day and 0.31 +/- 0.01 pools/day, respectively. In 10 hypertriglyceridemic patients with CHD, transport rates were 21.7 +/- 1.7 mg/kg-day, and FCRs averaged 0.56 +/- 0.06 pools/day; both were significantly higher than normal (P less than 0.05). Six normolipidemic patients also had abnormally high transport rates of LDL-apoB (19.4 +/- 2.8 mg/kg-day) and FCRs (0.51 +/- 0.03 pools/day); again both were higher than normal. The remaining 16 normolipidemic patients with CHD had normal transport rates (9.9 +/- 0.6 mg/kg-day) and FCRs (0.28 +/- 0.01 pools/day). Thus, hypertriglyceridemic patients with CHD and a portion of normolipidemic patients with CHD were characterized by increases in both transport and fractional catabolic rate of LDL-apoB; these abnormalities in LDL metabolism may have contributed to their coronary heart disease. However, the majority of normolipidemic patients with CHD did not show a distinct defect in their LDL metabolism.