Effects of estrogenic compounds on triglyceride kinetics.

Paired studies of triglyceride kinetics were made in 8 women on and off postmenopausal estrogen supplementation. When estrogens were discontinued, mean very-low-density lipoprotein triglyceride (VLD-TG) and VLD-TG turnover rate fell respectively from 555 to 349 mg/100 ml, and from 30-18 mg/kg/hr (p smaller than 0.01). Maximal turnover rate (Vmax) and VLD-TG concentration at 1/2 V max (Km), were 82.4 mg/kg/hr and 704.14 mg/100 ml on estrogen and fell to 41.83 and 347.51 when estrogen was discontinued (p smaller than 0.01). Estrogen supplementation did not lengthen VLD-TG half-life or diminish the fractional turnover rate of VLD-TG. Estrogens apparently increase VLD-TG by augmenting VLD-TG production rates.     

Effect of sex hormones on protamine inactivated and resistant postheparin plasma lipases.

Effects of estrogens and the synthetic anabolic-androgenic steroid, Oxandrolone, on extrahepatic (protamine inactivated) and hepatic (protamine resistant) lipases in postheparin plasma, were assessed in 15 subjects with familial hypertriglyceridemia. In six women receiving conjugated equine estrogen (1.25 mg/day), mean (+/- SE) postheparin protemine inactivated triglyceride lipase (PI-TGL) was depressed to 0.23 +/- 0.10 mumol FFA/ml/hr, and protamine resistant lipase was depressed to 5.3 +/- 0.5 mumol FFA/ml/hr. In the 2-wk period after estrogens were discontinued, PI-TGL remained depressed, 0.54 +/- 0.24, while PR-TGL increased to 7.3 +/- 0.88, p=less than 0.05. Mean triglycerides fell insignificantly from 628 +/- 136 to 447 +/- 44 mg/100 ml when estrogens were discontinued. There was no significant correlation between changes in PR-TGL and triglycerides when estrogens were stopped. In four women with familial hypertriglyceridemia, Oxandrolone significantly increased PR-TGL in two, increased PI-TGL in three, and reduced triglycerides in two. In five men with familial hypertriglyceridemia, Oxandrolone reduced triglycerides in four, increased PR-TGL in four, but had no effect on PI-TGL. For the nine hypertriglyceridemic subjects increments in PR-TGL failed to correlate significantly with decrements in triglyceride, (r=0.309, p is greater than 0.1). Selective alteration of PR-TGL and PI-TGL by estrogens and Oxandrolone may provide an approach to better understanding of the interaction of lipases and triglycerides in familial and acquired hypertriglyceridemia.     

Effects of probucol on plasma cholesterol,high and low density lipoprotein cholesterol,and apolipoproteins A1 and A2 in adults with primary familial hypercholesterolemia

This double-blind crossover study was designed to assess the safety, utility, and effectiveness of probucol (1000 mg/day) as an agent for reduction of total and low density lipoprotein plasma cholesterol (C-LDL) in 19 adults with primary familial hypercholesterolemia. The study was also designed to evaluate the effects of probucol on high density lipoprotein cholesterol (C-HDL) and its two major apolipoproteins, Apo A1 and Apo A2. After stabilization on a diet that provided < 200 mg cholesterol/day with a $\text{P}\text{S}$ ratio of 1.2:1, the subjects were randomized into the following drug-placebo sequences: 9 subjects received 24 wk of probucol followed by 24 wk of placebo, while 10 received 24 wk of placebo followed by 24 wk of probucol, with weight maintained ± 1 kg, and dietary cholesterol and $\text{P}\text{S}$ intake stable. In all 19 subjects on probucol total plasma cholesterol was reduced 10.7% and C-LDL 8.4% beyond the effects of diet alone; plasma triglyceride, the ratio of C-HDL to Apo A1, and the ratio of Apo $\text{A1}\text{Apo}$ A2 were not significantly changed. In all 19 subjects, the $\text{C-LDL}\text{C-HDL}$ ratio during probucol therapy was 22% higher than during placebo, with an overall 26% reduction in C-HDL on probucol as compared to placebo. In the group of 9 subjects, whose plasma C-HDL levels fell 19% on probucol, mean HDL apolipoprotein A1 (Apo A1) levels fell 6%, Apo A2 levels did not change. In the group of 10 subjects whose mean plasma C-HDL levels fell 30% on probucol, mean Apo A1 fell 34%, and Apo A2 fell 20%. The probucol was well tolerated, with mean adherence of 93%. Of the 19 subjects, the only drug-related side effects were diarrhea in two subjects, and fetid perspiration in another. The relevance of the simultaneous reduction in C-HDL in the face of a mean 8.4% reduction in C-LDL is unknown. Better long-term information about the prognostic significance for atherosclerotic disease of the reductions in C-HDL, Apo A1, and Apo A2 need to be obtained, in view of the inverse association of C-HDL with coronary heart disease.     

Nutrient intake: Relationships with lipids and lipoproteins in 6–19-year-old children—The Princeton School District study

Relationships between nutrient intakes and plasma lipids and lipoproteins were studied in 949 randomly selected children, ages 6–19, in the biracial, suburban, Princeton School District. While nutrient intake increased with age in males, such age-associated increases in nutrient ingestion were much less consistent or were not significant for females. Primarily in the 6–9 and 10–12 yr age groups, white children ingested more total calories, more saturated fat, and a lower ratio of polyunsaturated to saturated ($\text{P}\text{S}$) fat, more total carbohydrates, sucrose, starch, and other carbohydrates, and more protein than black children. After adjusting for age, race, sex, weight, and height, several nutrient-lipid and lipoprotein partial correlation coefficients were significant, but of relatively low magnitude. There were weak but significant inverse correlations between dietary $\text{P}\text{S}$ ratios and dietary carbohydrates with both total (r = ?.07, ?0.7) and low-density lipoprotein cholesterol (C-LDL), (r = ?.07, ?.08). Plasma high-density lipoprotein cholesterol (C-HDL) was inversely and significantly correlated with dietary sucrose (r = ?.07); plasma triglyceride correlated positively with dietary sucrose (r = .08). Potential relationships between nutrients and lipids-lipoproteins were also examined in children at the extremes of, and in the middle of, lipid-lipoprotein distributions. After covariance adjustment for age, sex, race, and Quetelet index, children having the highest levels of C-HDL had the lowest intake of dietary carbohydrate and total calories. After further covariance adjustment for total calories, children at the highest end of the plasma cholesterol distribution had a greater intake of cholesterol and total protein than did children in the lowest end of the distribution. Nutrient intake may play a small but significant role relative to lipids and lipoproteins in children, and as such, may have importance relative to pediatric precursors of atherosclerosis.     

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 ($\text{104–676}\text{mg}\text{100}\text{ml}$), 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<0.05, p<0.02, respectively) than the levels of the control subjects (208 ± 61 nmole/min/ml, n=11). The HTGL levels of the hemodialysis patients with ↑TG correlated inversely with plasma total cholesterol (r_s=−0.833, p<0.01) and the d>1.006 fraction cholesterol (low + high density lipoproteins, r_s=−0.863,p<0.01), but not triglyceride. The activity of HTGL of the entire group of hemodialysis patients correlated with the plasma total cholesterol (r_s=−0.615, p<0.01), d>1.006 fraction cholesterol (r_s=−0.731, p<0.01) and low density lipoprotein cholesterol (r_s=−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.     

Treatment of hypertriglyceridemia with para-aminosalicylic acid-C: A possible mechanism of action

The effect of para-aminosalicylic acid-C (PAS-C, 8 g/day) on lipid metabolism was studied on a metabolic ward in nine subjects with primary endogenous hypertriglyceridemia. During 2 wk on a basal isocaloric liquid formula diet (40% fat, 45% carbohydrate), PAS-C reduced plasma triglyceride (?41.9 ± 18.9%, p < .01, $\text{x}$ ± SD), cholesterol (?22.8 ± 12.9%, p < .005), and a very low density lipoprotein triglyceride (p < .001) and cholesterol (p < .01) levels without changing the cholesterol content of low density or high density lipoproteins. Similar effects occurred on a fat-free, 85% carbohydrate diet. Decreases in very low density lipoproteins correlated with changes in both total triglyceride (r = .99, p < .01) and cholesterol (r = .70, p < .05). Treatment with PAS-C reduced the plasma triglyceride removal rate related to lipoprotein lipase (?14.6 ± 14.1%, p < .02), but did not alter plasma postheparin lipolytic activity or the apparent Km for substrate-enzyme interaction. Kinetic data obtained during the prolonged heparin infusion fit the linearized Michaelis-Menten model for subjects with endogenous hypertriglyceridemia. The reduction in the plasma triglyceride concentration during PAS-C treatment was a function of the decrease in triglyceride removal rate (r = .74, p < .025) without alternation in the maximal removal capacity related to lipoprotein lipase. This suggests that under the steady state conditions of these studies, the decrease in plasma triglyceride concentration was due to a reduction in endogenous triglyceride production. Free fatty acid metabolism, glucose homeostasis, fat absorption, and thyroid function did not change. These results suggest that PAS-C lowers plasma triglyceride and cholesterol levels in hypertriglyceridemic subjects by reducing endogenous very low density lipoprotein production and/or secretion into the circulation.     

Hypertriglyceridemia and hypoalphalipoproteinemia in azoospermic and oligospermic young men: Relationships of endogenous testosterone to triglyceride and high density lipoprotein cholesterol metabolism

Based upon the hypothesis that endogenous testosterone plays a significant role in triglyceride and high density lipoprotein cholesterol metabolism, the specific aim of this study in 9 azoospermic and 10 oligospermic subjects (compared to 20 fertile men) was to examine potential relationships between endogenous testosterone, luteinizing hormone, follicle stimulating hormone, lipids-lipoproteins, and lipoprotein lipases. The azoospermic and oligospermic men had much higher fasting plasma triglyceride levels (mean ± SD; 479 ± 258, 295 ± 119) than did normal controls (105 ± 31 mg/dl, p < 0.001, p < 0.001). The azoospermic and oligospermic subjects also had much lower mean high density lipoprotein cholesterol levels (C-HDL) than normals (27 ± 8 and 29 ± 7 versus 44 ± 7 mg/dl, p < 0.001, p < 0.001). Very low density lipoprotein's (VLDL) in vitro potency to activate lipoprotein lipase (U/mg of VLDL protein) was about one-third normal in the azoospermic subjects (57 ± 26 U/mg), and about one-half normal in the oligospermic subjects (86 ± 27), with values in the normals being 167 ± 58, p < 0.001, p < 0.001. Mean plasma testosterone levels were 3.4 ± 0.7 ng/ml in the azoospermic subjects, considerably lower than mean levels in normals (6.6 ± 2.0, p < 0.001), with intermediate levels in the oligospermic men (5.2 ± 1.7 ng/ml). Pooling the data for the azoospermic, oligospermic, and normal men, plasma testosterone levels were positively correlated with C-HDL (r = .42, p < 0.01) and inversely correlated with triglyceride (r = ?.50, p < 0.001) and very low density lipoprotein cholesterol (r = ?.37, p < 0.02). Plasma testosterone was also positively correlated with lipoprotein lipase activator potency, (r = .45, p < 0.01). These findings suggest that endogenous physiologic testosterone levels may play a role relative to regulation of triglyceride and C-HDL levels in men, and may also affect the hydrolytic susceptability of very low density lipoprotein molecules. Hypertriglyceridemia and low C-HDL levels in azoospermic and oligospermic men mandate quantitation of lipid-lipoprotein levels in infertility clinics to identify men at putatively increased risk for future coronary heart disease.     

Bile sequestrant therapy alters the compositions of low-density and high-density lipoproteins.

Bile sequestrant resins are used to lower the levels of low-density lipoprotein cholesterol in plasma because this may ameliorate atherosclerosis. Yet the levels and compositions of all the lipoproteins may affect atherogenesis. We have previously shown alterations in very-low-density lipoprotein (VLDL) metabolism in response to one of these agents, colestipol HCl. Here we report the effects of colestipol on the composition of low-density and high-density lipoproteins (HDL). Eighteen subjects with type II hyperlipoproteinemia were studied during baseline, diet, and drug periods lasting 2–3 mo. Lipoprotein lipids and apolipoproteins A-I, A-II, and B were measured, and indices of lipoprotein composition were calculated. Colestipol produced significant changes in all lipoproteins. VLDL-triglyceride rose transiently, the magnitude and duration both correlated with pretreatment values (r = 0.84 and 0.76, respectively, both p < 0.001). Low-density (density 1.006–1.063) lipoprotein cholesterol fell below the dietary mean by 28%, but low-density triglyceride fell by only 13% and apolipoprotein B by 17%. Thus, low-density lipoprotein cholesterol/apolipoprotein B ratios decreased (1.9 versus 1.6, p < 0.005). Low-density and very-low-density cholesterol/apoprotein B ratios also decreased significantly. Thus, all the apolipoprotein-B-containing lipoproteins had less cholesterol relative to apolipoprotein B. High-density lipoprotein cholesterol remained unchanged, although transient increases in high-density lipoprotein triglyceride occurred. Apolipoprotein A-I levels remained constant (∼105 mg/dl), but A-II levels fell (from 55 to 45 mg/dl); therefore, $\text{A-I}\text{A-II}$ ratios rose (2.0 versus 2.5, p < 0.001). Thus, alterations in the composition of both high-density and low-density lipoproteins occurred. Colestipol produced changes in lipoprotein composition that may have effects on atherogenesis independent of its effects on lowering plasma cholesterol. Further studies will be needed to determine whether or not these changes are beneficial.     

Effects of hypophysectomy on sodium and water exchanges in the euryhaline flounder, Platichthys flesus (L)

In the hypophysectomized euryhaline flounder Platichthys flesus (L.) the ionic composition of the blood is almost normal in seawater (SW), but sodium and chloride levels are reduced in freshwater (FW), owing to increased extrarenal losses. Radioisotopic methods have been used to study the kinetics of sodium (²⁴Na) and water (tritiated water, HTO) balance in SW, $\text{1}\text{3}$ SW and FW.In SW sodium turnover, 45.1% exchangeable $\text{Na}\text{hr}$, and total ion efflux, 2760 μeq/hr/100g, of intact fish were reduced by one-fifth in hypophysectomized fish. It is probable that both the Na:Na and Na:K (Na pump) components of branchial exchange were depressed; maintenance of a normal blood sodium and renal ion efflux was indicative of a parallel reduction in intestinal ion uptake. An ACTH-cortisol deficiency may have been responsible for these effects. In $\text{1}\text{3}$ SW sodium turnover, 3.3%/hr, was similar in intact and ablated fish.The efficiency of the instantaneous regulation of sodium efflux on abrupt SW → FW transfer was reduced by hypophysectomy, leading to an increase in the residual passive efflux. During FW-adaptation following $\text{1}\text{3}$ SW → FW transfer branchial efflux attained stable levels in intact and ablated fish but was higher (+100% after 5 days) in the latter group. Influx was similar in the two groups, and, expressed both as an absolute flux and as $\text{f}{}_{\mathrm{in}}\text{Na}{}_{\mathrm{ext}}$ increased progressively. Intact fish achieved positive sodium balance, but ablated fish remained in negative balance due to the persistent high efflux. Though prolactin treatment did not repair this defect in long-term hypophysectomized fish, it did halve sodium turnover in intact, SW-adapted fish, an effect interpreted as a reduction in passive branchial sodium permeability. In intact fish in SW, HTO turnover (15.4%/hr) remained similar in $\text{1}\text{3}$ SW, and in FW (<1 week), but later increased (>1 week, 23.1% hr). In ablated fish the turnover values were similar and were not altered by prolactin treatment.Impaired sodium conservation in hypophysectomized fish in FW is due solely to a high branchial efflux; the sodium absorption pump and aqueous permeability are unaffected. These results are discussed in relation to studies on other hypophysectomized teleosts.     

Availability of apolipoprotein CII in relation to the maximal removal capacity for an infused triglyceride emulsion in man.

The aim of this study was to evaluate whether the transfer to triglyceride-rich particles of apolipoprotein CII is a quantitative determinant of triglyceride removal. An emulsion of triglyceride, Intralipid, which resembles chylomicrons in particle size but does not contain apolipoprotein, was infused at a constant rate for 1 hr in ten subjects with plasma triglyceride levels ranging from 40 to 636 mg/dl. During the infusion, samples were taken for measurement of particulate triglyceride by nephelometry and quantification of apolipoprotein content by polyacrylamide gel electrophoresis of reisolated particles. The maximal removal capacity for Intralipid-triglyceride, calculated as the infusion rate minus the linear increase in plasma Intralipid-triglyceride, was inversely related to the basal plasma triglyceride level. The apolipoproteins bound to Intralipid were apo CI, CII, and CIII. Apo A and apo E were not detected. The $\text{CII}\text{CIII}$ ratio was higher in larger triglyceride-rich particles (Intralipid) than in smaller ones (VLDL and HDL). The $\text{CII}\text{CIII}$ ratio in VLDL isolated before infusion was higher than in VLDL isolated 2 min after starting infusion. The amount of apolipoprotein CII bound to infused Intralipid increased in parallel to the increase in triglyceride level, with a constant $\text{CII}\text{TG}$ ratio between 2 and 60 min. The maximal removal capacity for infused Intralipid-triglyceride was not quantitatively related to the CII binding, expressed as $\text{CII}\text{TG}$. It is concluded that (1) the transfer of apolipoprotein CII from HDL, and also from VLDL, to large triglyceriderich emulsion particles entering the circulation occurs within minutes; (2) the availability of apolipoprotein CII for binding to continuously entering Intralipid particles is unlimited during 1 hr; (3) the amount of apolipoprotein CII bound does not control the rate of Intralipid-triglyceride removal from the plasma.     

Black--white differences in plasma lipoproteins in Cincinnati schoolchildren (one-to-one pair matched by total plasma cholesterol, sex, and age).

The suburban, biethnic Princeton School District provided a suitable population of children (ages 6–17) to test the hypothesis that black schoolchildren have higher high density lipoprotein cholesterol (C-HDL), lower low density lipoprotein cholesterol (C-LDL), and lower triglyceride levels than white schoolchildren when pair-matched by total plasma cholesterol, age, and sex. In 194 black-white pairs of male schoolchildren, black children had higher C-HDL (59.5 ± 13.5 versus 54.8 ± 12.7 mg/dl, p < .001), lower C-LDL (105.7 ± 25.8 versus 108.1 ± 26.7, p < .05), and lower triglyceride (60.7 ± 27.2 versus 71 ± 38.1, p < .001). In 222 black-white pairs of female schoolchildren, black girls had higher C-HDL (57.7 ± 13.1 versus 52.0 ± 11.6 mg/dl, p < .001), lower C-LDL (107.4 ± 24.8 versus 109.6 ± 23.3, p < .05, and lower triglyceride (64.0 ± 24.6 versus 80.2 ± 38.6, p < .001). Mean Quetelet indices (weight/height²) did not differ significantly for the black and white males or females. Since, by matching, the pairs did not differ in age, sex, or total plasma cholesterol, and also did not differ by Quetelet, any differences in C-HDL, C-LDL, and triglyceride can be imputed to racial or other unmeasured, racially related environmental differences in the cholesterol-carrying lipoprotein fractions. Persistence of these black-white differences in lipoproteins into adulthood may be associated with a relatively lower risk of coronary heart disease (CHD) in blacks than in whites, for any given total plasma cholesterol level.     

Age-related alterations in cardiac protein turnover

The influence of aging on cardiac protein turnover in rats was studied in vitro and in vivo. Hearts were perfused in vitro on a modified Langendorff perfusion apparatus with buffer containing cycloheximide to inhibit protein synthesis, and the rate of phenylalanine release into the perfusate was measured as an index of protein degradation. Phenylalanine release from hearts of $\text{1-}\text{to}\text{2}\text{1}\text{2}\text{-}\text{month-old}$ rats was 0.22 ± 0.013 nmol/mg wet wt/h compared to 0.16 ± 0.011 nmol/mg/h from hearts of 10- to 14-month-old animals (P < 0.005). This represents a 27% decrease in the rate of cardiac protein degradation in perfused hearts of older rats. When insulin was present in the perfusate the difference in cardiac protein degradation rates between animals in these age groups was similar (21% decrease in older animals, P < 0.01). Protein turnover in vivo was measured by the constant infusion technique using [¹⁴C]tyrosine. The fractional rate of cardiac protein degradation decreased from 14.8 ± 1.06%/day at $\text{1}\text{1}\text{2}$ months of age to 10.8 ± 0.91%/day at 12 months of age (P < 0.05). The rate of protein synthesis was also slower in the older rats, decreasing from 19.6 ± 1.63%/day at $\text{1}\text{1}\text{2}$ months to 10.8 ± 0.91%/day at 12 months (P < 0.005). In senile (24-month-old) hooded rats the fractional rates of cardiac protein synthesis and degradation were further reduced to 6.7 ± 0.29%/day compared to 12.4 ± 0.61%/day for 12-month-old rats of the same strain (P < 0.005). Thus, we conclude that cardiac protein degradation and synthesis decrease with aging.     

The effects of chronic uremia and dexamethasone on triglyceride kinetics in the rat.

The effects of chronic uremia and dexamethasone administration on triglyceride (TG) kinetics were studied in the rat. Uremia was produced by a two-stage, $\text{5}\text{6}$ nephrectomy, and resulted in a fourfold rise in BUN levels. The elevation in BUN level led to a rise in mean ( ± SE) TG levels from $\text{46 ± 4 to 62 ± 6 mg}\text{100 ml}$. The increase in TG levels was associated with a marked prolongation in very low density lipoprotein (VLDL) removal rate from plasma, without any change in triglyceride secretion rate (TG-SR). The combined effects of uremia and glucocorticoid treatment were evaluated by treating chronically uremic rats with either low (0.05 mg/kg body weight) or high (0.25 mg/kg body weight) doses of dexamethasone. The low dose of dexamethasone led to a further rise in mean TG levels of chronically uremic rats ($\text{107 ± 14 mg}\text{100 ml}$), and the hypertriglyceridemia was further accentuated when chronically uremic rats were treated with high-dose dexamethasone ($\text{179 ± 15 mg}\text{100 ml}$). The elevation of TG levels in uremic rats receiving the low dose of dexamethasone was associated with a prolongation of VLDL removal which was not statistically significant. Treatment with the higher dose of dexamethasone resulted in an increase in TG-SR and a further prolongation of VLDL removal, both of which were statistically significant. Thus, hypertriglyceridemia in the chronically uremic rat is due to a defect in VLDL removal. Dexamethasone treatment is capable of accentuating this removal defect, as well as increasing TG-SR. The combined effect of both is to lead to a marked degree of hypertriglyceridemia.     

Primary and familial hypoalphalipoproteinemia

Our specific aim was to assess within-family clustering of high-density lipoprotein cholesterol (HDLC) levels in kindreds identified through probands with primary hypoalphalipoproteinemia, and to determine whether, and to what degree, familial aggregation of HDLC ≤ the tenth percentile represents a heritable trait, familial hypoalphalipoproteinemia. Our probands were selected arbitrarily by virtue of HDLC ≤ the age-sex-race-specific tenth percentile as the sole dyslipoproteinemia, with an additional requirement that they be normotriglyceridemic (triglyceride levels < the 90th percentile). The probands were also required to have primary hypoalphalipoproteinemia, not secondary to diseases and/or drugs. Fifteen of the 16 probands were men; 12 were referred because of premature myocardial infarction, angina, or stroke, 2 because of family history of premature myocardial infarction or stroke, and 2 because of low HDLC observed on routine health examinations. Two of the 16 kindreds exhibited three-generation vertical transmission of bottom decile HDLC. In three kindreds, there was also three-generation vertical transmission of bottom decile HDLC, but top decile triglycerides accompanied bottom decile HDLC in one or more generations. Eight kindreds displayed two-generation vertical transmission of bottom decile HDLC. After excluding probands, there were 11 critical matings (bottom decile HDLC by normal), with 30 living offspring, all of whom were sampled. Of these 30 offspring, 13 had bottom decile HDLC, 17 had HDLC > tenth percentile. The ratio of offspring with bottom decile HDLC to those of HDLC > tenth percentile was 13:17 ($\text{0.76}\text{1}$), not significantly different from the ratio of $\text{1}\text{1}$, the ratio predictive of a dominant trait, X₁² = 0.53, P > 0.4. The nearly 1:1 segregation ratio for the group of offspring was not due to the aggregation of sibships with, in general, most of the sibs, or none of the sibs affected; within-family expression of low HDLC was also not sex-linked. The 13 hypoalphalipoproteinemic offspring of 11 critical matings included only two subjects whose bottom decile HDLC was accompanied by top decile triglyceride. Our data suggests that not only (by selection) was low HDLC in the probands the sole dyslipoproteinemia, but that the segregation of low HDLC in offspring of critical matings was primarily accounted for by isolated low HDLC, not by hypoalphalipoproteinemia secondary to hypertriglyceridemia. Familial hypoalphalipoproteinemia is a heritable disorder with a pattern of transmission not significantly different from that expected by a hypothesis of mendelian dominance. Irrespective of the more exact determination of a mode of inheritance of familial hypoalphalipoproteinemia, within-family aggregation of low HDLC as an isolated dyslipoproteinemia was associated with accelerated premature coronary heart disease and stroke in these 16 kindreds.     

Plasma lipoproteins, lipolytic enzymes, and very low density lipoprotein triglyceride turnover in Cushing's syndrome

Plasma lipoproteins, triglyceride turnover, and lipolytic enzymes were measured in 11 women with Cushing's syndrome. The studies were repeated 3 and 12 months after surgical treatment. Eleven healthy women of similar age and relative body weight served as controls. Before treatment the mean values of total cholesterol and triglyceride, of very low-density lipoprotein (VLDL) triglyceride and cholesterol, low density lipoprotein triglyceride and cholesterol, and high density lipoprotein cholesterol were all significantly increased in the patients with Cushing's syndrome. The triglyceride levels were only moderately elevated, the highest values being found in patients with adrenocortical adenoma. The production rate of VLDL triglyceride was higher in patients (13.2 mg/h . kg) than in controls (9.5 mg/h . kg, P less than 0.05), whereas the fractional catabolic rate of VLDL triglyceride was not significantly different. Consistent with the latter finding, the lipoprotein lipase activities of adipose tissue, skeletal muscle, and postheparin plasma were similar in patients and controls. The postheparin plasma hepatic lipase activity of the patients was at the lower end of the normal range. All lipid and lipoprotein abnormalities were completely abolished after successful surgery. It is concluded that endogenous hypercortisolism stimulates the hepatic production of VLDL particles. The effect is probably based on multifactorial mechanisms. In the presence of unchanged removal this leads to elevated levels of VLDL, low density lipoprotein, and high density lipoprotein.     

Impaired very low density lipoprotein and triglyceride removal in broad beta disease: comparison with endogenous hypertriglyceridemia.

The removal rate of apoprotein-B (apo B) in very low density lipoprotein (VLDL) was decreased in individuals with broad beta disease when compared with endogenous hypertriglyceridemia. Following the injection of 125I-VLDL isolated from individuals with endogenous hypertriglyceridemia, both VLDL apo B fractional catabolic rate (0.058 +/- 0.029 hr-1) and VLDL apo-B turnover rate (0.300 +/- 0.070 mg/kg/hr) were lower in broad beta disease than in endogenous hypertriglyceridemia (fractional catabolic rate 0.112 +/- 0.046, p less than .05; turnover rate 0.640 +/- 0.199, p less than .005) despite equivalent plasma concentrations of VLDL-apo-B. Furthermore, conversion of VLDL apo-B to LDL was impaired in broad beta disease relative to endogenous hypertriglyceridemia. Differences in the kinetics of lipoprotein lipase-related triglyceride removal during a maximal heparin infusion were also demonstrated between these two disorders. These differences suggest an abnormality in the interaction of lipoprotein lipase with the lipoproteins of unusual composition in broad beta disease. This is further supported by the normalization of lipoprotein composition in broad beta disease by estrogen therapy, with a simultaneous change in the kinetics of lipoprotein lipase-related triglyceride removal towards those seen in endogenous hypertriglyceridemia.     

Plasmalemmal vesicles in pulmonary capillary endothelium of developing fetal lamb lungs

In adult mammalian lungs pinocytotic vesicles (PV) play a role in macromolecular transport across endothelium. The time course of their development in fetal lungs was examined. Morphometric techniques were used to measure the relative capillary volume as percentage of lung volume. Mean diameter ($\text{D}$), numerical density (N_v), and endothelial fractional volume (V_v) represented by PV were determined in randomly selected capillaries, measuring 5.3–8.4 μm in diameter, from right upper (RUL) and left lower (LLL) lobes of lungs from fetal lambs ranging in gestational ages from 39 to 144 days. Three newborn lambs, 1 hr after birth, were also examined. There was a 20-fold increase in the volume density of capillaries during the period studied. The vesicular $\text{D}\text{±}\text{SD}$ was 739.6 ± 4.1 and 735.1 ± 2.8 Å in RUL and LLL, respectively, and remained unchanged throughout gestation. By contrast, following a gradual increase in N_v from 24.7 to 65.1/μm³ in the glandular stage (39–85 days), there was a rapid rise in N_v during both canalicular (95–121 days) and alveolar (130–144 days) stages of development, reaching a final N_v of 254.8/μm³. In newborn lambs, 1 hr after birth, there was no significant change in N_v. There was a significant correlation between N_v and fetal age, but there was no difference in N_v between RUL and LLL at any time. Thus, a more than 10-fold increase in N_v of PV occurs in ovine pulmonary capillary endothelium during gestation, the biochemical and/or physiological basis of which remains to be determined. By contrast, observations made on coated vesicles indicate that N_v of these structures does not change with gestation.     

The effects of hypothyroidism,age, and nutrition on LDL catabolism in the rat

To determine the effects of thyroid deficiency on LDL metabolism and degradation, the plasma clearance of ¹²⁵I-LDL was determined in normal rats and rats fed chow containing propylthiouracil (PTU) 0.1% w/w and KI $\text{0.16 gm}\text{1}$ in the drinking water. After two weeks, T₄ levels were significantly lower in the PTU groups compared to controls and plasma LDL cholesterol increased from $\text{17.5 ± 1.2}{}^1\text{1}\text{Results given as mean ± SEM.}\text{mg}\text{100 ml}$ in controls to $\text{32.5 ± 3.0 mg}\text{100 ml}$ in the hypothyroid animals. Human ¹²⁵I-LDL (d 1.019–1.045) was injected intravenously under light anesthesia and tail tip blood was sampled repeatedly over 33–100 hr periods. In a semi-log plot the curve of ¹²⁵I-LDL clearance described a log-linear profile suggesting a two-pool model. Compartmental analysis according to Matthews revealed two exponential curves, an initial rapid phase representing equilibration with an extravascular compartment (exponential 2), and a later slow phase of irreversible degradation (exponential 1). There was a marked delay in clearance of ¹²⁵I-LDL in the hypothyroid rats as the slope of exponential 1 was 0.043 ± 0.001 ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{= 16.2 hr}$) versus 0.065 ± 0.002 ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{= 10.7 hr}$) in controls (P < 0.01). Additionally, the fractional catabolic rate of LDL was reduced (P < 0.01) from 0.079 ± 0.003 in normals to 0.054 ± 0.002 (pools/hr) in hypothyroid rats. The delay in LDL clearance which occurred in hypothyroidism occurred in both growing and mature rats. Pair-feeding excluded any artifact due to the weight loss commonly seen in hypothyroid rats. LDL clearance was age-dependent as the slope of exponential 1 was significantly lower in mature (521 ± 3 gms) as compared to growing (256 ± 12 gm) rats. Experiments performed after a 24 hr fast showed that acute starvation did not affect LDL clearance. The data suggest that the hypercholesterolemia of hypothyroidism is at least partly secondary to an acquired catabolic defect of LDL, and implies that the LDL catabolic pathway(s) is influenced by thyroid hormones.     

Apolipoprotein AI and AII metabolism in patients with primary high-density lipoprotein deficiency associated with familial hypertriglyceridemia

Plasma high-density lipoproteins (HDL) and their major proteins--apolipoprotein (apo) AI and apo AII--are subnormal in most patients with familial hypertriglyceridemia. However, the pathophysiology of low-plasma apo AI and apo AII is unclear. The kinetic parameters (turnover) of HDL apo AI and apo AII were studied in six lean patients with primary HDL deficiency associated with familial hypertriglyceridemia and five normolipidemic controls. Autologous 125I labeled HDL were injected intravenously (IV; 25 microCi) and blood samples drawn ten minutes after the injection and periodically thereafter for 12 days. Urine samples were collected daily and their radioactivity measured. Kinetic parameters were calculated from the area under the decay curve using three exponentials. Mean plasma apo AI and apo AII were significantly lower (P less than 0.001) in patients than normals (70.4 +/- 2.7 v 106.9 +/- 7.0; 24.2 +/- 1.6 v 39.2 +/- 0.9 mg/dL, respectively). The mean fractional catabolic rates (FCR) obtained from plasma 125I-HDL, apo AI, apo AII radioactivity decay curves and by Berson and Yalow's method (urine/plasma radioactivity ratios) were significantly greater (P less than 0.05) in patients than in controls (0.387 v 0.299; 0.391 v 0.309; 0.361 v 0.275; 0.272 v 0.207/d; respectively). The mean synthetic rates (SR) of apo AI and apo AII were significantly lower in patients than in controls (11.12 v 14.17 mg/kg body weight/d, P less than 0.05; 3.53 v 4.68 mg/kg body weight/d, P less than 0.05, respectively). In vitro lipolysis of triglyceride (TG) rich lipoproteins by bovine lipoprotein lipase, and measurement of hepatic TG lipase and lipoprotein lipase in postheparin plasma were similar in patients and controls, indicating no abnormality in these factors that are linked to HDL and TG catabolism. However, a significant positive correlation between hepatic TG lipase and the FCR of apo AI and apo AII was found. The data suggest that in this series of patients with HDL deficiency the low plasma HDL-cholesterol, apo AI, and apo AII levels resulted from decreased synthesis and an increased fractional catabolic rate of apo AI and apo AII, the major proteins of HDL.     

Cholesterol-free diet and the physiologic hyperlipidemia of pregnancy in familial hypercholesterolemia

Longitudinal studies of the effects of a cholesterol-free diet and a less rigid 300 mg/day low cholesterol diet, both with a polyunsaturated to saturated fatty acid ratio of $\text{1.8}\text{1}$, were carried out preconception, during gestation, and postpartum in a woman heterozygous for familial hypercholesterolemia. On the cholesterol-free diet, during weeks 8–14 of gestation, plasma cholesterol was lowered 25% (from 310 to 230 mg/dl), and plasma low density lipoprotein cholesterol (C-LDL) (from 240 to 160 mg/dl), 33%. The 25% reduction in plasma cholesterol was slightly more than prviously reported decrements of 19% in 14 normal women during pregnancy, also receiving a cholesterol-free diet. The 300 mg cholesterol diet was not as hypocholesterolemic as the cholesterol-free diet. Its maintenance throughout gestation limited the within-pregnancy increments of total plasma cholesterol and C-LDL to 21% (352–426 mg/dl) and 14% (286–326 mg/dl) respectively. Both the cholesterol-free and the 300 mg cholesterol diet were well tolerated, and should be nutritionally adequate for pregnant women, since they contain more than the recommended amounts of high quality protein, vitamins, minerals, and calories for pregnant women. Cholesterol restricted diets during pregnancy in familial hypercholesterolemics should reduce the physiologic hypercholesterolemia of pregnancy, and potentially reduce the increased risk of coronary heart disease relative to the degree and duration of elevations of total and LDL cholesterol.