Plasma triglyceride metabolism in thyroid disease.

Plasma endogenous triglyceride transport kinetics were determined in 16 hyperthyroid and in 12 hypothyroid patients and the results compared with those of euthyroid control subjects. In addition, the removal of exogenous particulate fat (Intralipid; Vitrum, Sweden) from the circulation and the postheparin plasma lipolytic activity (PHLA) were studied in these patients for further characterization of the alterations of plasma triglyceride metabolism in thyroid disease. In thyrotoxicosis the average plasma triglyceride level was slightly but significantly increased above that of control subjects. This change was associated with augmented production of triglycerides whereas the mean fractional removal rate was not different from normal. There was a significant linear correlation between the concentration and turnover rate of plasma triglycerides in both hyperthyroid and euthyroid subjects but the concentration/turnover rate ratio was less in the former group suggesting that the efficiency of removal of triglycerides from the circulation was improved in thyroid hyperfunction. The elimination of intravenously administered particulate fat occurred more rapidly in untreated hyperthyroid patients than in euthyroid control subjects. The mean PHLA was also above normal in thyrotoxicosis. Upon adequate treatment of the hyperthyroid state the fasting plasma triglyceride concentration was further increased. Hypothyroid patients showed another pattern of alteration of triglyceride kinetics. The synthesis of plasma triglycerides was normal but the fractional removal of both endogenous and exogenous triglycerides was markedly reduced and this change seems to account for the hypertriglyceridemia associated with thyroid hypofunction. The plasma PHLA was also clearly decreased in the hypothyroid state. Plasma FFA and glycerol levels were increased in hyperthyroidism and plasma FFA was slightly decreased in hypothyroid patients, but these variables were not significantly correlated with any parameter of triglyceride metabolism. Endogenous triglyceride turnover rate was significantly correlated with serum protein-bound iodine (PBI) and T3 uptake in thyrotoxicosis but not in hypothyroidism. Removal of exogenous fat was not related to postheparin plasma lipolytic activity but the fractional endogenous triglyceride transport showed a highly significant relationship to this lipase activity in a mixed group of hyper- and hypothyroid patients. The results suggest that thyroid hormones control both production and removal of plasma triglycerides. Different mechanisms for these interactions are considered.

Characterization of lipase activities in obese Pima indians. Decreases with weight reduction.

Adipose tissue and muscle lipoprotein lipase and postheparin hepatic and lipoprotein lipase activities have been measured in a group of 21 Pima Indian males over a wide range of body weight to determine the relationship between obesity and these lipase activities. There was a significant positive correlation between adipose tissue lipoprotein lipase and obesity; muscle and postheparin lipoprotein lipase and hepatic lipase were not related to degree of obesity. Fasting insulin levels were not related to any of the measurements of lipase activity. There were racial differences in adipose and postheparin lipoprotein lipase activities; both were significantly lower in the Pimas as compared with a group of weight-matched Caucasian males. Lipase activities were remeasured in eight subjects after a period of weight reduction including several weeks of stabilization at the reduced weights. After the period of weight reduction adipose tissue lipoprotein lipase declined in all subjects. Hepatic lipase also declined in all but two patients. Muscle and postheparin lipolytic activities were not affected by weight loss. The data indicate that (a) there are racial differences in adipose tissue lipoprotein lipase; and (b) the elevated adipose lipoprotein lipase associated with obesity, like many other biochemical variables in the obese state, returns toward normal after weight reduction.

Cholesterol exchange between fat cells, chylomicrons and plasma lipoproteins.

Isolated rat adipocytes were incubated with serum lipoproteins or lymphchylomicrons which contained 14c-labeled cholesterol. The specific activity of lipoprotein free cholesterol decreased and that of cellular free cholesterol increased linearly up to 7 h. At this time the cell cholesterol specific activity was only 11% of that of medium cholesterol indicating that the rate of exchange was slow. The specific activity of lipoprotein esterified cholesterol remained unchanged while that of cells showed a slight increase suggesting esterification of incorporated free cholesterol. No detectable change of the lipoprotein or cellular cholesterol concentration occurred indicating that the uptake of radioactive free cholesterol was due to exchange without net movement of sterol. The radioactive cholesterol was incorporated into both membrane fraction and the fat droplet of the adipocytes. The rate of cholesterol exchange was temperature-dependent but it was not influenced by the metabolic state of the cells and not by addition of metabolic inhibitors. Trypsin or pronase treatment of the cells were without influence on the rate of the exchange and denaturation of the plasma lipoproteins with formalin increased the rate of exchange. These results indicate that the exchange of cholesterol is a physical chemical process, which is not linked to energy metabolism of the cells, and which is not mediated by either specific lipoprotein receptors on fat cell membranes or pinocytic uptake of lipoproteins. The rate of free cholesterol exchange showed a linear correlation with the concentration of lipoprotein particles in the medium. The relative transfer rate was highest for chylomicrons and decreased in order chylomicron remnants greater than very low density lipoprotein greater than low density lipoprotein greater than high density lipoprotein. A saturation of the system could be obtained only with high density lipoprotein.

Ethanol-induced alterations of glucose tolerance, postglucose hypoglycemia, and insulin secretion in normal, obese, and diabetic subjects.

Ethanol at an average blood concentration of 1 mg. per milliliter enhanced the immediate (first-phase) and prolonged (second-phase) insulin response to an intravenous glucose load in nonfasting normal human subjects. Simultaneously, the glucose disposal rate was increased and the postglucose hypoglycemia was accentuated, resulting in definite hypoglycemic symptoms in some individuals. Oral glucose tolerance was not changed by ethanol administration, but the thirty-minute blood glucose and plasma insulin values were increased, suggesting that alcohol might accelerate the absorption of glucose from the gut. Ethanol given orally during evening hours (1.5 gm. per kilogram) caused a nocturnal hyperinsulinemia and a decrease of blood glucose, but not an actual hypoglycemia. Oral glucose tolerance and plasma insulin response tested the next morning, when ethanol had disappeared from the blood, were not influenced by drinking the previous evening. The K-value of intravenous glucose was increased at this time, however. When alcohol was administered for one week at a dose corresponding to 25 per cent of daily calories and substituting for fat, both the oral and intravenous glucose tolerances were impaired in each subject but the insulin response remained unchaged. In obese nondiabetic subjects, ethanol did not potentiate the early insulin response to intravenous glucose but it increased the second phase of insulin secretion in response to sustained hyperglycemia. In contrast to conditions in nonobese subjects, the glucose disposal rate was not incresed and postglucose hypoglycemia was not accentuated by ethanol in overweight subjects. In insulin-deficient diabetic patients the absent early insulin response could not be restored by ethanol, and the late component of insulin release was little increased by alcohol infusion. Ethanol did not improve the glucose utilization of diabetic patients.

Postheparin plasma lipoprotein lipase and hepatic lipase in diabetes mellitus. Relationship to plasma triglyceride metabolism.

The activity of two triglyceride lipases was determined by an immunochemical method in the postheparin plasma of 60 diabetic patients and of 47 age- and sex-matched nondiabetic control subjects. The results were related to the type of diabetes, to plasma triglyceride and insulin concentrations, to removal of exogenous fat from the blood, and to turnover of VLDL-triglycerides . The mean postheparin plasma lipoprotein lipase (LPL) activity was decreased by 44 per cent (p less than 0.001) in patients with untreated ketotic diabetes and by 20 per cent (p less than 0.01) in patients with untreated mild to moderate nonketotic early-onset diabetes. Insulin treatment of ketotic diabetes resulted in a rapid increase in the activity of LPL and decrease in serum triglycerdie level, whereas sulfonylurea treatment of non-insulin-requiring diabetics did not significantly influence the enzyme activity. In insulin-treated chronic diabetics the average postheparin plasma LPL activity was not different from that of nondiabetic controls, but some of these patients had high LPL values. In normolipidemic maturity-onset-type diabetics the LPL activity was within normal range, but in those having hypertriglyceridemia the average LPL value was decreased by an average of 26 per cent (p less than 0.01). The LPL activity showed a significant negative correlation with the logarithm of serum triglyceride concentration (r = -0.62) and a positive correlation with fractional removal of Intralipid (r = +0.64) and fractional turnover of V triglyceride (r = +0.40). The activity of LPL was correlated to basal plasma insulin concen tration in the insulin-deficient diabetes r = +0.34) but not in patients with maturity-onset-type diabetes. The hepatic lipase (HL) activity of postheparin plasma was similar in diabetes and controls, with the exception of hypertriglyceridemic maturity-onset diabetics, who had higher mean HL activity than the corresponding control group (p greater than 0.01). The activity of HL was not related to triglyceride removal but showed a significant correlation to VLDL-triglyceride production rate. On the basis of these results it seems that a deficiency of LPL accounts for a great deal of the elevation of serum triglyceride in insulin-deficient human diabetes but has a smaller role in the pathogenesis of the hypertriglyceridemia that is associated with maturity-onset diabetes. The latter abnormality is caused mainly by an increased secretion of triglycerides into the blood even though a decreased LPL may contribute to development of hyperlipemia in cases with gross elevation of serum triglycerides.

Bedtime insulin for suppression of overnight free-fatty acid, blood glucose, and glucose production in NIDDM.

We studied the clinical effectiveness and mechanism underlying the glucose-lowering effect of evening insulin therapy. Nocturnal profiles of blood glucose, plasma free fatty acid (FFA), glycerol, and lactate and overnight glucose kinetics [( 3-3H] glucose infusion) were measured in 15 non-insulin-dependent diabetic (NIDDM) patients with a relative body weight of 128 +/-4% who were poorly controlled with oral therapy alone. The patients were studied before and 2 wk and 3 mo after bedtime insulin (23 +/- 3 IU) was given in addition to oral therapy. An early-morning rise in blood glucose (greater than 31 mg/dl = 1.5 mM) was present in two-thirds of the patients and was associated with an overnight rise in plasma FFA and an increase in glucose production (Ra) during the early-morning hours (change 0.42 +/- 0.10 mg.kg-1.min-1, P less than .05, between 0300 and 0800). The overnight mean levels of blood glucose, plasma FFA, and serum insulin averaged 212 +/- 9 vs. 137 +/- 11 vs. 133 +/- 11 mg/dl (P less than .001), 674 +/- 61 vs. 491 +/- 57 vs. 484 +/- 36 microM (P less than 0.01) and 12.7 +/- 1.6 vs. 18.1 +/- 2.2 vs. 20.7 +/- 2.4 microU/L (P less than .01) before and 2 wk and 3 mo after the combination therapy. The decrements in overnight glucose and FFA levels after 2 wk of bedtime insulin therapy were closely correlated (r = .86, (P less than .001). The nocturnal profile of plasma lactate was similar before and during bedtime insulin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum lipids and lipoproteins in insulin-dependent diabetic subjects during high-carbohydrate, high-fiber diet.

The response of blood glucose and serum lipids and lipoproteins to a high-carbohydrate, high-fiber, low-fat diet was assessed in 10 insulin-dependent diabetic subjects. The diet contained approximately 60% of calories as carbohydrate (CHO) and 20% as fat. The patients were followed for 2 wk in a metabolic ward and subsequently for 4 wk at home without changing insulin dosage. During this 6-wk period, the fasting blood glucose fell from 10.6 +/- 1.1 to 8.9 +/- 1.3 mmol/L (NS); HbA1 fell from 11.7 +/- 0.5 to 11.0 +/- 0.7% (P less than 0.05). Serum total triglyceride and very-low-density lipoprotein levels remained unchanged. After 2 wk in the ward on a high-CHO diet, total cholesterol fell by 15% (P less than 0.01), LDL cholesterol by 16% (P less than 0.001), and HDL cholesterol by 10% (P less than 0.05). The fall of HDL cholesterol was due to a decrease of HDL3 cholesterol only. After the 4-wk home period on a high-CHO diet, the observed lipoprotein changes were reversed. Heparin-releasable adipose tissue LPL activity was not influenced by a high-CHO diet. In conclusion, a high-carbohydrate, high-fiber, low-fat diet did not deteriorate the diabetic control, and it had no unfavorable effects on serum lipids or lipoproteins.

Ethanol decreases glucose utilization in healthy man.

The effect of ethanol on glucose utilization during hyperinsulinemia was studied by the euglycemic clamp technique. Normal subjects were given 1 g ethanol/kg body weight for 210 min (oral priming dose of 0.67 g/kg followed by iv infusion of 0.33 g/kg) or 0.9% saline. Insulin infusion, started 90 min after the beginning of ethanol administration, resulted in a mean plasma insulin concentration of 87 +/- 5 (SEM) mU/liter. Plasma glucose was maintained at 5.2 mmol/liter. The rate of glucose metabolism was 23% lower during ethanol (7.1 +/- 0.1 mg/kg X min) than during the control (9.0 +/- 0.8 mg/kg X min) experiment (P less than 0.001). During hyperinsulinemia blood lactate concentrations rose in the control study but this change was abolished by ethanol. The insulin-induced fall of serum triglyceride levels was also inhibited by ethanol. It is concluded that acute intake of alcohol in moderate doses induces insulin resistance.

Lipoproteins, lipolytic enzymes, and hormonal status in hypothyroid women at different levels of substitution.

Serum lipoproteins and postheparin plasma lipoprotein lipase and hepatic lipase (HL) activities were determined in 23 hypothyroid women treated with graded doses of thyroxine (T4) (50, 100, and 150 micrograms/day), each given for 3 weeks. Since the sex hormone-binding globulin (SHBG) and thereby serum sex steroid concentrations are sensitive to thyroid status, we also measured serum testosterone, estradiol, and SHBG at each time. Stepwise T4 treatment resulted in gradual improvement in thyroid status. Concomitantly, serum low density lipoprotein (LDL) cholesterol decreased in a linear fashion from a mean of 4.72 +/- 0.31 (+/- SEM) to 3.21 +/- 0.18 mmol/L (P less than 0.001) after the largest dose. In contrast, serum high density lipoprotein (HDL) cholesterol decreased, although not in a dose-dependent fashion, from 1.61 +/- 0.07 to 1.44 +/- 0.05 mmol/L (P less than 0.001) after the largest dose. Serum SHBG increased along with improvement of thyroid function, but this increase did not have major impact on the changes in LDL during T4 treatment, as judged by multiple regression analysis. Thus, serum LDL correlated independently only with T4 (r = -0.38; P less than 0.001). The serum HDL changes were almost exclusively due to those in the HDL2 subfraction, and these were related to HL activity, which increased from 13.4 +/- 1.76 to 18.9 +/- 2.08 U/L after the largest dose. We conclude that thyroid hormones regulated serum HDL (HDL2) cholesterol mainly through their effect on HL.

Short-term effects of prednisone on serum lipids and high density lipoprotein subfractions in normolipidemic healthy men.

To study the effects of short term low dose prednisone administration on serum lipids and lipoproteins we measured the concentration and composition of serum lipoproteins; serum apoproteins (apo) A-I, A-II, and B; and plasma lipolytic enzymes before and during prednisone administration (30 mg/day for 7 days) in eight normal men. We also measured insulin binding to adipocytes. Serum high density lipoprotein (HDL) cholesterol increased significantly after 2 days of prednisone administration; the maximal increase was 27% (P less than 0.01 after 5 days). The rise of HDL cholesterol was accounted for by that of HDL2 cholesterol. There were marked changes in the distribution of HDL particles; HDL2 increased, whereas HDL3 decreased. These changes were also apparent after 2 days of prednisone administration and were maximal at 5 days [mean, 1.58 +/- 0.12 (+/- SE) vs. 2.00 +/- 0.14 g/L (P less than 0.001) for HDL2; 1.82 +/- 0.11 vs. 1.61 +/- 0.06 g/L (P less than 0.05) for HDL3], and they were due to opposing changes in cholesterol, phospholipids, and proteins in the HDL subfractions. The change in HDL2 protein correlated inversely with that in HDL3 protein (r = -0.73; P less than 0.05). Notably, prednisone did not change the apo A-I concentration, but that of apo A-II decreased (0.32 +/- 0.02 vs. 0.27 +/- 0.01 g/L; P less than 0.05). Consequently, the lipid to protein ratio of HDL increased. Prednisone induced no significant changes in very low density or low density (LDL) lipoproteins. Adipose tissue LPL activity did not increase until after 7 days of prednisone intake (1.10 +/- 0.28 vs. 3.43 +/- 1.02 mumol FFA/g.h; P less than 0.05), and the same was true for muscle LPL (0.49 +/- 0.14 vs. 0.82 +/- 0.11 mumol FFA/g.h; n = 4; P = 0.06). Specific insulin binding was normal, but both basal and maximal insulin-stimulated glucose transport decreased significantly. In summary, prednisone induces changes in serum HDL which are characterized by redistribution of particles within HDL density toward less dense particles and a quantitative rise of lipids in the HDL2 fraction.

Severity, duration, and mechanisms of insulin resistance during acute infections.

Acute infections provoke insulin resistance. These experiments were designed to study the severity, duration, and mechanisms of insulin resistance caused by acute infections. First, we studied eight patients [mean age, 29 +/- 11 (+/- SD) yr; body mass index, 23 +/- 2 kg/m2] with acute viral or bacterial infections during the acute stage of their infection and 1-3 months after recovery. The rate of glucose infusion required to maintain normoglycemia during hyperinsulinemia (approximately 500 pmol/L) was used as a measure of insulin action. During infection, the glucose requirements in the patients [21 +/- 2 (+/- SE) mumol/kg.min] were 52% less than those in weight- and age-matched normal subjects (44 +/- 2 mumol/kg.min; P less than 0.001). Compared to data from a large group of normal subjects, the resistance to insulin during infection corresponded to that predicted for a weight-matched 84-yr-old normal person or an age-matched obese person with a body mass index of 37 kg/m2. One to 3 months after recovery, the patients' glucose requirements were still significantly lower (37 +/- 3 mumol/kg.min; P less than 0.02) than those in matched normal subjects. To assess the mechanism of insulin resistance, seven additional patients were studied during the acute stage of infection using a low dose insulin infusion (plasma insulin, 215 pmol/L) combined with a [3-3H]glucose infusion and indirect calorimetry. Again, the glucose requirements were 59% lower in the patients (14 +/- 2 mumol/kg.min) than in matched normal subjects (34 +/- 2 mumol/kg.min; P less than 0.001). This decrease was due to a defect in glucose utilization (18 +/- 2 vs. 37 +/- 1 mumol/kg.min; P less than 0.001, patients vs. normal subjects) rather than impaired suppression of glucose production (4 +/- 1 vs. 3 +/- 1 mumol/kg.min, respectively). Total carbohydrate oxidation rates were similar in both groups (16 +/- 2 vs. 14 +/- 1 mumol/kg.min, respectively), whereas the apparent glucose storage was neglible in the patients (2 +/- 1 mumol/kg.min) compared to that in normal subjects (22 +/- 2 mumol/kg.min; P less than 0.001). We conclude that acute infections induce severe and long-lasting insulin resistance, which is localized to glucose-utilizing pathways. The rate of carbohydrate oxidation is normal during infections, whereas the rate of nonoxidative glucose disposal, as determined by indirect calorimetry, is nearly zero. The apparent blockade in glucose storage could result from diminished glycogen synthesis, accelerated glycogenolysis, or both.

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.

High density lipoprotein-2 and hepatic lipase: reciprocal changes produced by estrogen and norgestrel.

The concentrations of plasma high density lipoprotein (HDL) and its subfraction HDL2 are influenced by endogenous and exogenous sex hormones. The catabolism of HDL2 is mediated by a lipolytic enzyme, hepatic lipase, which is present in endothelial cells covering the liver sinusoids. Since the activity of this enzyme is also regulated by gonadal and anabolic steroids, we examined whether the effect of sex steroids on plasma HDL is related to changes in hepatic lipase. In postmenopausal women, estradiol valerate (2 mg/day, orally) increased the HDL2 cholesterol and phospholipid concentrations by 20% (P less than 0.05). Simultaneously, the hepatic lipase activity of postheparin plasma decreased by 25% (P less than 0.05). The addition of levonorgestrel (250 micrograms/day, orally) to the treatment reversed both effects of estrogen, so that HDL2 cholesterol and phospholipid levels fell below and hepatic lipase activity rose above the respective pretreatment values. The hormones did not influence the HDL3 lipid concentrations or the lipoprotein lipase and lecithin:cholesterol acyltransferase activities. The results are compatible with the hypothesis that the effects of sex steroids on plasma HDL (HDL2) are mediated by changes in hepatic lipase activity.

Site of insulin resistance in type 1 diabetes: insulin-mediated glucose disposal in vivo in relation to insulin binding and action in adipocytes in vitro.

To evaluate the mechanism of insulin resistance in type 1 diabetes mellitus, we measured insulin sensitivity in vivo and insulin action in adipocytes in vitro. The study groups consisted of 18 insulin-treated type 1 diabetic patients and 14 matched normal subjects. In each subject, insulin-mediated glucose disposal in vivo was measured by the euglycemic clamp technique. An open surgical biopsy was performed in 9 diabetic and 7 healthy subjects to obtain abdominal sc adipose tissue for the measurement of [125I]insulin binding, D-[14C]-glucose transport, oxidation, and lipogenesis. During the euglycemic clamp studies, similar steady state plasma glucose (4.8 mmol/liter) and insulin (80 mU/liter = 700 pM) levels were maintained in both groups. The rate of glucose metabolism (M) was 43% lower in the diabetic patients (4.75 +/- 0.34 mg/kg X min) than in the normal subjects (8.27 +/- 0.43 mg/kg X min; P less than 0.001). [125I]Insulin binding to adipocytes was reduced in the diabetic patients (26% reduction in tracer binding; P less than 0.05) due to a reduction in receptor number. Insulin binding was not related to the M value at any insulin concentration. Basal and insulin-stimulated rates of glucose transport were not significantly different in diabetic and normal subjects. The basal glucose oxidation rate was reduced by 50% (P less than 0.02), and maximal glucose oxidation was reduced by 49% (P less than 0.03) in the diabetic patients (237 +/- 30 vs. 359 +/- 49 pmol/30,000 cells X 90 min, basal vs. maximal glucose oxidation, respectively) compared to those in normal subjects (513 +/- 101 vs. 700 +/- 133 pmol/30,000 cells X 90 min). The percentage responses of glucose oxidation and glucose transport to insulin were similar in both groups. Glucose oxidation rates at basal (r = 0.68; P less than 0.01), half-maximally (ED50; r = 0.70; P less than 0.01), and maximally (r = 0.64; P less than 0.05) effective insulin concentrations were positively related to the M value. Basal and insulin-stimulated rates of lipogenesis were comparable between the diabetic and normal subjects. In conclusion, insulin-mediated glucose disposal in vivo is reduced in conventionally treated type 1 diabetic patients. In vitro, adipocytes from diabetes bound slightly less insulin at tracer insulin concentrations, but the magnitude of this reduction was not related to impairment of glucose metabolism in vivo. Of the pathways of glucose metabolism studied, the rate of glucose oxidation was most affected. A significant relationship was found between the M value and the rate of in vitro glucose oxidation.(ABSTRACT TRUNCATED AT 400 WORDS)

Very low density lipoprotein triglyceride kinetics during hepatic lipase suppression by estrogen. Studies on the physiological role of hepatic endothelial lipase.

The exact role of the heparin-releasable hepatic endothelial lipase has remained controversial. It has been suggested that it acts in concert with lipoprotein lipase in the step-wise delipidation of triglyceride-rich lipoproteins. On the other hand, there is evidence indicating that high density lipoprotein2 is the preferred substrate for hepatic lipase. Here, it is shown that a moderate (27%) suppression of hepatic lipase activity by estrogen did not impair removal of 3H-labeled very low density lipoproteins (VLDL) triglycerides, suggesting that this enzyme is not a major regulator of VLDL catabolism under physiological circumstances.

Effects of acipimox on serum lipids, lipoproteins and lipolytic enzymes in hypertriglyceridemia.

Two separate studies were carried out with acipimox, a new antilipolytic agent with long-lasting activity. First, in a randomized, double-blind, cross-over study a dose of 750 mg/day of acipimox versus placebo was employed for 60 days in 11 patients with type IV hyperlipoproteinemia. Mean plasma triglyceride levels were reduced after acipimox compared to placebo (434 +/- 60 vs 777 +/- 224 mg/dl, P less than 0.01). Serum total cholesterol fell also significantly after acipimox compared to placebo. No significant alteration was observed in the HDL2/HDL3 ratio or in the concentration or composition of the HDL subfractions. Six patients with severe hypertriglyceridemia (2 type IV and 4 type V) and low lipoprotein lipase (LPL) activity took part in a second, open study, lasting for 9 months. Acipimox was given at a dose of 750 mg/day for the first 6 months and 1200 mg/day for the last period. The response of serum total and VLDL triglycerides was inconsistent. HDL cholesterol was significantly raised (+33.3%) after 9 months of treatment due to changes of HDL2 and HDL3 cholesterol, phospholipid and protein concentrations. LPL activity was markedly reduced in adipose tissue at 9 months. No significant changes occurred in postheparin plasma LPL activity. In contrast, hepatic lipase activity showed a reduction of about 25% from 6 months of treatment onwards.

Serum lipoproteins in patients with myocardial infarction.

The lipid and lipoprotein profile was examined in male patients with acute myocardial infarction (AMI) at the time of infarction (group A) and in male patients who had survived AMI 2-3 years before the study (group B), and compared to that of healthy controls. The myocardial infarction (MI) patients exhibited similar total cholesterol and LDL-cholesterol levels as the controls. However, the LDL mass concentration was higher in patients than in controls (P less than 0.01 for group A, P less than 0.001 for group B). In composition, patients' LDL in both groups was rich in protein and triglycerides but poor in cholesterol. The compositional changes in patient LDL were evident at all levels of LDL-cholesterol. The mean total HDL and HDL2 mass concentrations were lower in patients than in controls (P less than 0.001 for both groups), but there was no difference in HDL3 levels. Upon admission to hospital the patients with AMI at the time of examination (group A) had higher serum total triglyceride concentration than controls, but on the fasting morning samples serum triglyceride and VLDL lipid levels did not differ between patients and controls. Patients who had survived AMI 2-3 years prior to study (group B) exhibited higher serum total triglyceride and VLDL levels than the control subjects. On stepwise discriminant analysis, HDL2 protein concentration was the single best variable for distinguishing between patients and controls. The most powerful discriminatory parameter was the HDL/LDL protein ratio or the HDL2/LDL protein ratio.

Effects of caloric restriction on lipid metabolism in man: changes of tissue lipoprotein lipase activities and of serum lipoproteins.

Heparin-releasable lipoprotein lipase (LPL) activity was measured in biopsy samples of adipose tissue and skeletal muscle of 8 normal healthy females, first during an isocaloric diet and then after 2 and 7 days on a 400-kcal diet. In adipose tissue the LPL activity expressed per tissue weight fell to 38% and to 22% of the initial level after 2 and 7 days' caloric restriction, respectively. In skeletal muscle the LPL activity rose slightly after two days (+24%) but decreased to 49% of the initial value after seven days on diet. The estimated total body LPL activity decreased to 50% and to 20% of the baseline value after 2 and 7 days, respectively, but the relative contribution of skeletal muscle to the total LPL increased from 10 to 30%. The triglyceride and VLDL triglyceride concentrations were not significantly changed during the low calorie diet but the LDL triglyceride increased and the HDL cholesterol decreased significantly (P less than 0.01). It is concluded that substantial restriction of calorie intake results in a decrease of over-all triglyceride removal capacity but in an increase of the fraction removed by skeletal muscle. The decrease of HDL cholesterol is probably a consequence of the low turnover of exogenous and endogenous triglyceride-rich lipoproteins.

Identification of the high-risk groups in familial coronary heart disease.

Occurrence of coronary heart disease (CHD) was assessed among the sibs of 309 men with fatal or non-fatal CHD, including 126 men who developed the disease before age 46 (young patients), and 183 men who developed it at age 46-55 (middle-aged patients), and among the sibs of 212 reference men. The risk of early onset CHD was about 3 times as great for the sibs of the young as for those of the middle-aged patients. The risk was greatest of all, or up to 10-fold over the expected value, for the sibs of those young patients whose father or mother had died of CHD before age 70, but the risk was distinctly increased also for the sibs of the other young patients. By contrast, the sibs of the middle-aged patients carried an appreciably increased risk of early onset CHD only when one of the parents had died from CHD before age 70. Information about the family pattern of CHD is helpful in identifying the individuals at high risk for premature CHD.

Immunochemical assay of rat postheparin plasma triacylglycerol lipases.

Immunochemical methods for selective measurement of lipoprotein lipase and hepatic lipase activities in rat postheparin plasma are described and validated. Lipoprotein lipase was measured using a substrate containing 10% serum and 0.1 M NaCl after inactivation of hepatic lipase with a specific antiserum. Hepatic lipase was measured at 1.0 M NaCl with a serum-free substrate. The heparin dose-response curve indicated maximum relase of both activities at a heparin dose of 500 IU/kg. The lipase activities in rat postheparin plasma were 3 to 4-fold higher than those in human postheparin plasma. The LPL activity in female rats was significantly higher than in males whereas there was no sex difference for hapatic lipase.