Deborah Applebaum-Bowden

Reduction of lecithin-cholesterol acyltransferase, apolipoprotein D and the Lp(a) lipoprotein with the anabolic steroid stanozolol

The effects of the anabolic steroid stanozolol (17-methyl-2H-5 alpha-androst-2-eno-(3,2-c)pyrazol-17 beta-ol) on lecithin-cholesterol acyltransferase, apolipoproteins B and D and the Lp(a) lipoprotein were determined in a prospective study of ten normolipidemic women with postmenopausal osteoporosis. Lecithin-cholesterol acyltransferase was reduced approx. 30% by 6 weeks of treatment with stanozolol (off treatment 5.1 +/- 1.2, on treatment 3.4 +/- 0.8 muml; P less than 0.02). The Lp(a) lipoprotein was reduced 65 +/- 23% by the steroid treatment (off treatment 5.5 +/- 5.5, on treatment 1.4 +/- 0.7 mg/dl; P less than 0.02). Apolipoprotein D was reduced 23 +/- 9% by the treatment (off treatment 5.9 +/- 0.9, on treatment 4.5 +/- 0.7 mg/dl; P less than 0.02). In contrast, apolipoprotein B increased slightly but insignificantly on steroid therapy (off treatment 90 +/- 21, on treatment 112 +/- 24 mg/dl). By 5 weeks after the drug was discontinued, all four of these proteins were near pretreatment levels. These significant changes in lipoprotein metabolism, combined with our previous report of reductions of HDL and particularly HDL2, suggest the need for caution in the long-term use of anabolic steroids.

Studies on the metabolic mechanism of reduced high density lipoproteins during anabolic steroid therapy

To explore the mechanism whereby stanozolol, a 17 alpha-methyl androgenic anabolic steroid, depresses high density lipoproteins (HDL), 6 subjects, aged 46-71 yr (4 postmenopausal women and 2 men), underwent paired studies of 125I-HDL turnover (including HDL2 and HDL3 and Apo A-I and A-II) and postheparin plasma (PHP) lipolytic activity (hepatic triglyceride lipase, HTGL, and lipoprotein lipase LPL) before and during treatment with stanozolol, 6 mg/day. While total cholesterol and triglyceride levels did not change during stanozolol, HDL-cholesterol decreased from 59 +/- 18 mg/dl (x +/- SD) to 29 +/- 7 mg/dl (p less than 0.01) and low density lipoprotein (LDL)-cholesterol increased from 160 +/- 36 mg/dl to 181 +/- 42 mg/dl (p less than 0.02). PHP-HTGL increased from 111 +/- 47 nmole/min/ml to 369 +/- 202 nmole/min/ml (p less than 0.04), while PHP-LPL did not change. At baseline the residence time of HDL2 (4.00 +/- 1.04 day) was shorter than that of HDL3 (6.79 +/- 1.00 day) (p less than 0.001). Residence times of both declined on stanozolol, to 3.25 +/- 0.83 day and 4.00 +/- 0.29 day, respectively (0.1 less than p less than 0.2); however, only the reduction in residence time of HDL3 was statistically significant (p less than 0.001). At baseline the residence time of apo A-I (4.93 +/- 1.32 day) was shorter than that of A-II (6.85 +/- 1.98 day) (p less than 0.025); on stanozolol these declined to 3.19 +/- 0.41 (p less than 0.02) and 5.10 +/- 1.13 (p = 0.07), respectively, still significantly different from each other (p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction in high density lipoproteins by anabolic steroid (stanozolol) therapy for postmenopausal osteoporosis.

The effects of stanozolol, 17-methyl-2H-5 alpha-androst-2-eno [3,2-c] pyrazol-17 beta-ol, on lipoprotein levels were assessed in a short-term (6 wk) prospective study of 10 normolipidemic, postmenopausal, osteoporotic women. While total cholesterol and triglyceride levels remained constant, equal and offsetting responses were seen in low density lipoprotein (LDL) cholesterol (+30.9 +/- 28.1 mg/dl [mean +/- S.D.], p less than 0.01, a 21% increase) and high density lipoprotein (HDL) cholesterol (-32.5 +/- 11.9 mg/dl [mean +/- S.D.], p less than 0.001, a 53% decline). Hence the LDL/HDL ratio increased dramatically, from 2.5 +/- 0.7 to 6.8 +/- 2.5. Within HDL, stanozolol was associated with a greater decline in HDL2 (from 26.0 +/- 7.4 mg/dl to 3.8 +/- 1.9 mg/dl, p less than 0.001, an 85% decrease) than HDL3 (which diminished from 35.7 +/- 3.2 to 24.1 +/- 5.8 mg/dl. p less than 0.001, a 35% decrease). The major HLD apolipoproteins also declined (A-I by a mean of 41% and A-II by 24%, both p less than 0.001). Postheparin hepatic triglyceride lipase increased (off treatment 74 +/- 42 nmole free fatty acid min-1 mole-1, on treatment 242 +/- 110, n = 6, p = 0.06). All changes were reversed by 5 wk following termination of the drug. These lipoprotein changes suggest caution in the long term prescription of stanozolol, particularly in those without overriding clinical indications for its use.

Postheparin plasma triglyceride lipases. Relationships with very low density lipoprotein triglyceride and high density lipoprotein2 cholesterol.

Hepatic triglyceride lipase (HTGL) and lipoprotein lipase (LPL) probably have major roles in the removal of triglyceride from triglyceride-rich lipoproteins and in the formation of high density lipoprotein (HDL). However, no population-based study of their activity and relationship to lipoprotein lipid levels has been reported. To determine these relationships, we recalled 33 men and 17 women of a randomly selected sample of the Lipid Research Clinics Pacific Northwest Bell Telephone Company Health Survey. The subjects were 53 ± 7 years old (mean ± SD) with total triglyceride levels of 120 ± 57 mg/dl and total cholesterol levels of 224 ± 35 mg/dl. Postheparin plasma LPL activity (127 ± 61 nmol/min/ml) was not significantly correlated with either age, sex, or adiposity. In contrast, HTGL activity was significantly higher in men (235 ± 84 nmol/min/ml) than women (170 ± 91 nmol/min/ml, p < 0.02), and was correlated with age in men and with adiposity in women. In both men and women, HTGL activity was related positively with VLDL triglyceride and inversely with HDL2 cholesterol. When the association between HTGL activity and VLDL triglyceride was examined with values from men and women pooled, the relationship was not weakened after adjustment for the linear effect of sex, adiposity, LPL, or HDL2 cholesterol.

Epidemiological correlates of high density lipoprotein subfractions, apolipoproteins A-I, A-II, and D, and lecithin cholesterol acyltransferase. Effects of smoking, alcohol, and adiposity.

Recent data suggest that the protection against ischemic heart disease afforded by high density lipoprotein (HDL) cholesterol (C) may be concentrated in the HDL2 subfraction. To examine the behavioral correlates of the HDL subfractions, we recalled 33 men and 17 women of a random sample from the Pacific Northwest Bell Telephone Company Health Survey. Adiposity and very low density lipoprotein (VLDL) triglyceride were negatively correlated with HDL2C. Smoking was not correlated with HDL2C, but was negatively correlated with HDL3C (men, rs = −0.635, p = 0.001; women, rs = −0.534, p 0.014); this relationship was independent of alcohol consumption, adiposity, and VLDL triglyceride. Alcohol consumption was also more strongly related to HDL3C (men, rs = 0.248, p = 0.082; women, rs = 0.586, p = 0.007). Lecithin cholesterol acyltransferase (LCAT) mass was negatively related with HDL2C, but was positively correlated with HDL3C and apolipoprotein A-II. Smoking was negatively correlated with LCAT mass. Since it is believed that HDL3C is not associated with the risk of ischemic heart disease and since both smoking and alcohol consumption may mainly affect HDL3C, the current study suggests that the increase in risk of ischemic heart disease with smoking and the possible decrease with alcohol consumption may be mediated through mechanisms other than their effects on HDLC.

The dyslipoproteinemia of anabolic steroid therapy: increase in hepatic triglyceride lipase precedes the decrease in high density lipoprotein2 cholesterol.

Administration of the androgenic anabolic steroid, stanozolol, is associated with decreased high density lipoprotein (HDL) cholesterol (primarily due to decreased HDL2 cholesterol) and increased levels of postheparin plasma hepatic triglyceride lipase (HTGL) activity. Since HTGL appears to play a role in HDL metabolism, we examined the temporal relationship between these changes. HDL cholesterol remained stable during the first two days of stanozolol administration, but decreased 14% (P less than .01) by the third day and 39% (P less than .01) by the seventh day of stanozolol. HDL2 cholesterol paralleled the total HDL cholesterol level and remained stable for the first two days, but decreased 22% (P less than .01) after three days and 71% (P less than .01) after seven days of stanozolol. In contrast, HTGL increased 62% (P less than .001) during the first day, 161% (P less than .001) with two days, 230% (P less than .001) with three days of stanozolol administration, and remained elevated thereafter. Thus, during stanozolol administration HTGL increased dramatically and clearly before any change in HDL or HDL2 cholesterol.

Postheparin plasma triglyceride lipases in chronic hemodialysis: Evidence for a role for hepatic lipase in lipoprotein metabolism

Elevated plasma triglyceride levels frequently occur in patients with chronic renal failure receiving longterm hemodialysis. Postheparin plasma lipolytic activity, an indirect measure of triglyceride removal, is low in hemodialysis patients, but this activity measures both hepatic triglyceride lipase (HTGL) and lipoprotein lipase (LPL). To determine if HTGL and/or LPL are low in hemodialysis patients and related to lipoprotein lipid levels, both activities were measured by a selective antibody-inhibition technique in postheparin plasma from 20 hemodialysis patients with a wide range of plasma triglyceride levels (104–676 mg100 ml), and the relationships between the enzyme activities and lipoprotein lipid levels were examined. To more accurately compare subjects, the heparin doses were adjusted for the differences in plasma volumes between the hemodialysis patients and the nonuremic control subjects. Hemodialysis patients with elevated plasma triglyceride levels (↑TG) had HTGL levels (148 ± 67 nmole/min/ml, n=10) which were similar to the dialysis patients with normal triglyceride levels (nlTG) (134 ± 64 nmole/min/ml, n=10) and both groups were significantly lower (p 1.006 fraction cholesterol (low + high density lipoproteins, rs=−0.863,p 1.006 fraction cholesterol (rs=−0.731, p<0.01) and low density lipoprotein cholesterol (rs=−0.659, p<0.01). The LPL levels of the hemodialysis patients with the ↑TG (52 ± 24 nmole/min/ml) were lower than those with nlTG (70 ± 25 nmole/min/ml) and the levels of both hemodialysis groups were significantly lower (p<0.01, p<0.02, respectively) than the LPL levels in the control subjects (110 ± 43 nmole/min/ml). The ratio of LPL to total postheparin plasma lipolytic activity was lower in the hemodialysis patients with ↑TG (0.32 ± 0.15), than in the hemodialysis patients with nlTG (0.47 ± 0.18, p<0.06) or the control subjects (0.45 ± 0.09, p<0.05). Unlike HTGL, the levels of LPL did not correlate with lipid levels in the hemodialysis patients. Thus, both postheparin plasma HTGL and LPL are low in hemodialysis patients. The relationship between HTGL and low density lipoprotein cholesterol levels suggests a possible role for HTGL in low density lipoprotein catabolism.

Preliminary report: kinetic studies on the modulation of high-density lipoprotein, apolipoprotein, and subfraction metabolism by sex steroids in a postmenopausal woman.

To investigate the effects of estrogens and androgens on the metabolism of high density lipoproteins (HDL) and low density lipoproteins (LDL), a normolipidemic postmenopausal woman was studied under the following conditions: (1) during supplementation with ethinyl estradiol (0.06 mg/d); (2) without sex steroid therapy; (3) during treatment with stanozolol, an androgenic, anabolic steroid (6 mg/d). During these manipulations HDL and LDL cholesterol levels fluctuated widely but reciprocally: during estrogen supplementation HDL increased while LDL decreased; during stanozolol HDL-C decreased while LDL-C increased. Simultaneous changes in post-heparin plasma hepatic triglyceride lipase activity paralleled those of LDL (and opposed those of HDL), decreasing with estrogen and increasing with stanozolol. During all three phases, autologous 125I-HDL turnover studies disclosed similarities between HDL2 and apolipoprotein A-I metabolism and between HDL3 and apolipoprotein A-II metabolism. In the untreated state the residence times of HDL2 and apo A-I were only half those of HDL3 and apo A-II. During estrogen treatment HDL2 and apo A-I, residence times were selectively prolonged, coming to resemble those of HDL3 and apo A-II, which remained unchanged. By contrast, during stanozolol treatment HDL3 and apo A-II residence times were selectively reduced, coming to resemble those of HDL2 and apo A-I, which remained unchanged. Apo A-I levels increased on estrogen and decreased on stanozolol, while apo A-II remained stable. Hence, estrogen increased HDL primarily by retarding the catabolism of the HDL2 subfraction rich in apo A-I, whereas stanozolol decreased HDL by accelerating the catabolism of HDL3, relatively rich in apo A-II.(ABSTRACT TRUNCATED AT 250 WORDS)

Short-term egg yolk feeding in humans: Increase in apolipoprotein B and low density lipoprotein cholesterol☆

In animal studies, hypercholesterolemia induced by cholesterol feeding results in the plasma cholesterol being transported by lipoproteins of lower densities. Little information is available for humans. To determine the specific lipoprotein responses to dietary cholesterol challenge in humans, four volunteer subjects ingested a liquid formula diet containing 5000 mg of egg yolk cholesterol per day for 30 days and the changes in their lipoprotein fractions were examined. The high dietary cholesterol (above the range of normal diet) was associated with marked increases in apolipoprotein B and low density lipoprotein (LDL) cholesterol levels. An elevated cholesterol : triglyceride ratio in the LDL fraction indicated that the diet altered both LDL level and composition. High density lipoprotein cholesterol and apolipoprotein AI increased slightly. Very low and intermediate density lipoprotein cholesterol and apolipoprotein E levels did not increase during the diet. Thus, high dietary cholesterol was associated with major changes in LDL level and composition, but only minor changes in the other lipoprotein fractions and suggested only minor accumulation of remnant particles.

Effects of Diet and Age on Lipoprotein Lipase and Hepatic Triglyceride Lipase Activities in the Rat

Abstract Plasma clearance of triglyceride-rich lipoproteins appears decreased in aged humans and rats and may be due to lowered activities of the lipases responsible for lipid degradation. This study was designed to examine differential effects of age and diet on lipoprotein lipase (LPL) activity of adipose and heart tissue and hepatic triglyceride lipase (HTGL) activity. LPL and HTGL activities were examined in 3- and 13-month-old Sprague-Dawley rats after they had consumed either a high-carbohydrate or a high-fat diet for 14 days. The data were analyzed for age and diet differences by two-way analysis of variance. Although animals in the two age groups consumed diets of equal caloric content, the older rats gained less weight. Rats on the high-carbohydrate diet consumed less calories and gained less weight than the fat fed rats in both age groups. Neither heart nor adipose tissue LPL activity differed when examined for age or diet. HTGL activity levels, while not affected by age, were higher in the carbohydrate fed rats (P = 0.014). Regardless of age group, fasting plasma cholesterol levels were significantly higherin the carbohydrate-fed rats than fat-fed rats (P = 0.002). Thus, the diet effect was much stronger than the age effect for HTGL and plasma cholesterol levels.