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The concept that an inherent absence of plasma LDLs may be associated with a reduced synthesis of steroid hormones has been evaluated in two patients with ABL. Basal production of adrenal corticosteroids, assessed by the concentrations of serum cortisol and the rates of excretion of urinary 17OHCS and 17KS and urine free cortisol, was normal in both patients with ABL. Prolonged stimulation (24 to 36 hr) with ACTH, however, disclosed an impairment in adrenal corticosteroid production in both patients with ABL (as compared to normolipidemic controls), which was manifest by lower serum cortisol levels, reduced rates of urinary excretion of 17OHCS and 17KS and a marked decrease in the excretion of urine free cortisol. These results provide in vivo evidence to support the view that plasma LDLs serve as an important source of cholesterol for adrenal corticosteroid synthesis during prolonged stimulation with ACTH but show that a total absence of LDL does not impair adrenal steroidogenesis in the basal state.

Cholesterol turnover was measured in 5 normal subjects and 14 familial hypercholesterolemic (Type II) patients. All patients were fed eucaloric cholesterol-free or very low cholesterol formula or mixed-food diets. They were given single doses of cholesterol-1,2-3H and cholesterol-4-14C simultaneously, one isotope intravenously (IV), and the other orally. Plasma cholesterol specific radioactivity decay curves for 3H and 14C isotopes in each patient conformed to the short-term (10 to 12 weeks) kinetics of the two-pool model. In type II patients, the total mass of cholesterol in pool A was significantly larger by about 17 Gm. (by the IV method) and 27 Gm. (by the oral method) as compared with normal subjects. The increase in size of pool A in Type II patients occurred equally in plasma and tissues comprising pool A (probably liver and intestine). The rate constant for the excretion of cholesterol from pool A was significantly reduced in the Type II patients. The rate constant for the transfer of cholesterol from pool A to pool B was also reduced in the Type II patients. Furthermore, the metabolic clearance fraction was decreased by 50 per cent as compared with normal subjects. In normal subjects and in Type II patients, the size of pool A was significantly larger by about 5 Gm. and 15 Gm., respectively, by the oral method as compared with the IV method. This difference in the size of pool A probably reflects differences in isotopic equilibration with the intestinal mucosal cholesterol pool. All other parameters of cholesterol turnover by the IV method as compared with the oral method were similar. Our results suggest that the expanded rapidly exchangeable pool of cholesterol (pool A) is due to a defect in cholesterol transport and excretion in familial hypercholesterolemia (Type II). The decreased rate of removal of cholesterol from the plasma and/or catabolism in tissues could be one important cause of familial hypercholesterolemia in man.

The turnover of xanthoma cholesterol was measured in 9 hyperlipidemic and one normocholesterolemic patients. Sequential biopsies of the xanthomas were obtained 13 to 364 days after the administration of isotopic cholesterol and were then analyzed for cholesterol specific activity. A total of 34 xanthomas of 3 different types - 10 tendon xanthomas, 3 tuberous xanthomas, and 21 xanthelasmas - comprised the material for analysis. The cholesterol specific activity ratio of tendron xanthomas to that of the plasma varied from 11 per cent at 21 days to a maximum of 543 per cent at 122 days after the intravenous administration of isotopic cholesterol. This ratio declined to 426 per cent at 182 days and was still 131 per cent at 364 days. Similarly, the cholesterol specific activity of xanthelasmas increased gradually. In most instances, the xanthelasma cholesterol attained isotopic equilibration with plasma cholesterol by about 50 days but varied from patient to patient (minimum time, 46 days and maximum time, 91 days). The cholesterol content of xanthomas ranged from 10.7 to 197.0 mg per gram of dry weight of the tissue. Sixty-one to 87 per cent of the total xanthoma cholesterol was esterified. No other sterols were identified in these xanthomas. Thus, the cholesterol of 3 types of xanthoma readily attained isotopic equilibration with the plasma cholesterol which suggested total exchangeability of cholesterol between plasma and xanthomas. The uptake of cholesterol by the xanthomas from plasma was rapid considering the large mass of cholesterol in the lesions. The turnover of xanthoma cholesterol was intermediate between that of the rapidly exchangeable pool and of the slowly exchangeable pool of body cholesterol. Comparison of these results with those obtained in human advanced atheroma suggest that the turnover of xanthoma cholesterol and atheroma cholesterol are quite different.

Eight normotensive white middle-aged men were given low, moderate, and high salt diets with constant potassium intakes each for periods of at least 4 weeks. There was a tendency for body weight, serum sodium, exchangeable sodium, and inulin space to increase. Indirect blood pressure measurements revealed no change in blood pressure, either supine or upright measurements, during the 3 study intervals. Inulin clearance (and presumably glomerular filtration rate) rose with increase in dietary salt. Urinary potassium excretion rose progressively as salt intake increased. Total body potassium tended to decrease with increase in dietary salt. There was no changes in the excretion of calcium, magnesium, phosphorus, nor were there changes in the blood level of potassium. There was no change in total body water. The serum cholesterol and triglyceride levels were not appreciably affected by the different dietary sodium intakes. Plasma renin activity and urinary aldosterone excretion rose progressively with the two levels of sodium restriction. These studies indicate that normal man is able to compensate for large differences in sodium intake with minor metabolic changes. These changes do not necessarily lead to hypertension over a one-month period. Nevertheless, many hemodynamic and hormonal compensatory mechanisms come into play. It is evident that hypertension might result should the sodium load not be excreted, the circulating volume become too great for the excretory capacity, or if neural or endocrine adjustments be inadequate.

The metabolism of the small pool of triglyceride in human high-density lipoproteins (HDL) has been studied. In 28 postabsorptive and unmedicated subjects the previously reported reciprocal relationships between the concentration of very low-density lipoprotein (VLDL) lipids and HDL cholesterol was confirmed. It was also found that the HDL triglyceride correlated positively and significantly with the concentration of VLDL triglyceride, and there was a significant negative correlation between the concentrations of triglyceride and cholesterol in HDL. Five normal and 3 hypertriglyceridemic subjects were given 5,000 units of heparin intravenously. Not only was there a pronounced reduction in VLDL triglyceride, but there was a 60 to 80 per cent reduction in HDL triglyceride; the low-density lipoprotein (LDL) triglyceride was unchanged. To test a possible precursor-product relationship between the triglyceride pools in VLDL and HDL, 5 subjects were given an intravenous pulse injection of (14-C)-palmitic acid. The specific activity-time curves of triglyceride in VLDL and HDL did not conform to a typical precursor-product relationship; rather the HDL curve reached its peak well before it crossed the VLDL curve, quite compatible with an origin of HDL triglyceride which was independent of VLDL. However, when the lipoproteins of density smaller than 1.006 (VLDL and chylomicrons) were labeled in the intestine after an oral tracer dose of (3-H)-palmitic acid in 2 subjects, the relationship of the triglyceride labeling in HDL to that in d smaller than 1.006 lipoproteins was very similar to the relationship observed after the intravenous dose. Although an independent intestinal origin of HDL triglyceride could not be excluded, this result did suggest that the labeling of triglyceride in d smaller than 1.006 lipoproteins and in HDL was related and was consistent with a transfer from the larger lipoproteins to the HDL. In three subjects given a constant intravenous infusion of (3-H)-palmitic acid, the specific activity of triglyceride in VLDL became constant after 3 to 4 hours; it also became constant in the HDL after about 4 hours but at a level of only 40 to 70 per cent of the VLDL level. It appeared that 30 to 60 per cent of the HDL triglyceride was either derived from an unlabeled source or else turned over too slowly to become labeled to any extent during the infusions. Whatever the explanation, the same phenomenon would be likely to influence the level of the peak specific activity of HDL triglyceride after the pulse intravenous injections of label. It is possible that the specific activity of the "labeled" fraction of HDL triglyceride may have reached its peak at the point at which it crossed the VLDL curve, which would be consistent with a precursor-product relationship between VLDL and one fraction of the HDL triglyceride. It has been concluded that HDL triglyceride is heterogeneous and includes at least one pool, possibly transferred from VLDL, which is relatively rapidly turning over.