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Gastric mucosal prostaglandin E2 and F2 alpha content was evaluated in healthy human subjects who received either fish oil or olive oil (control) daily for 3 wk before exposure to aspirin or no aspirin. Two hours after aspirin administration, when mean serum salicylate concentration was approximately 12 mg/dl, gastric mucosal prostaglandin E2 and F2 alpha content was reduced by greater than 95% in the fundus and antrum (p less than 0.001) and there was endoscopic evidence of gastric mucosal damage (erosions, submucosal hemorrhages). Fish oil feeding had no significant effect on mucosal prostaglandin E2 or F2 alpha content or on the damaging effect of aspirin on the stomach, despite the fact that fish oil reduced serum triglyceride concentrations significantly. These studies indicate that the damaging effects of aspirin on the gastric mucosa are not influenced by dietary fish oil.

A patient is described who has marked palmar xanthomatosis associated with a normal concentration of plasma cholesterol. Analysis of xanthomas revealed them to contain large quantities of cholesterol with both intra- and extracellular lipids. Examination of plasma lipoproteins showed them to be consistent with a pattern of dysbetalipoproteinemia (Type III hyperlipoproteinemia). VLDL had beta-mobility on electrophoresis, a high cholesterol/triglyceride ratio, and increased apoprotein B. However, arginine-rich apoprotein was not increased in VLDL, in contrast to hypercholesterolemic patients with the Type III pattern. Nevertheless, the E3 subfraction of the arginine-rich apoprotein was virtually absent, which is characteristic of dysbetalipoproteinemia. Cholesterol and bile acid synthesis were in the normal range. Thus, of particular interest was the development of severe xanthomatosis without hypercholesterolemia in this patient. Therefore, tissue accumulation of cholesterol was apparently the result of a qualitative abnormality in lipoproteins and not due to an excess of plasma cholesterol.

The rate of biliary bile acid excretion is a product of bile acid pool size and enterohepatic cycling frequency. Cycling frequency, in turn, is determined by the time necessary for bile acid to travel from the ampulla of Vater to its small bowel absorptive site, from its absorptive site to the liver, and from the liver to the duodenum. In 10 subjects receiving constant intraduodenal infusion of an isocaloric formula containing the nonabsorbable markers polyethylene glycol and beta-sitosterol, the authors altered small intestinal transit time and measured the effect upon biliary bile acid excretion rate. Sorbitol (15% formula) shortened transit time by 38% and increased hourly bile acid excretion rate by 31%. Atropine (0.04 mg i.m. q 2 hr) increased transit time by 38% and decreased hourly bile acid excretion rate by 38%. Biliary excretion rates of cholesterol and of bilirubin, substances excreted in bile but not subject to enterohepatic circulation, did not change with changes in transit time. This suggests that sorbitol and atropine were not acting upon the biliary limb of the enterohepatic circulation but rather on the intestinal limb. The authors conclude that small bowel transit time is a major determinant of enterohepatic cycling frequency.

Subjects in the National Cooperative Gallstone Study undergoing 12 mo of therapy with chenodeoxycholic acid for the dissolution of gallstones (low-dose, 375 mg/day, n =252; high-dose, 750 mg/day, n = 253) had a mean increase in serum cholesterol of 20 mg/dl as compared with a 5 mg/dl increase in the placebo group (n = 258). The effect of chenodeoxycholic acid on lipoproteins was determined in a random subset of the high-dose (n = 136) and placebo (n = 143) groups. For men, the mean baseline adjusted estimated low-density lipoprotein cholesterol level at 12 mo was significantly higher in the high-dose group than in the placebo group (159 vs. 148 mg/dl, p less than 0.01), whereas among women this difference was not demonstrated. Change in low-density lipoprotein cholesterol level was inversely related to baseline cholesterol to an equivalent degree in each group among men and women. Women in the high-dose group had significantly lower very-low-density lipoprotein cholesterol levels than did the corresponding placebo group (27 vs. 32 mg/dl, p less than 0.003). Very-low-density lipoprotein cholesterol levels did not differ significantly between the high-dose and placebo group in men. Treatment did not significantly affect the levels of high-density lipoprotein cholesterol or apoproteins A-I, A-II, or B. Chenodeoxycholic acid therapy produces an increase in total cholesterol and low-density lipoprotein cholesterol but does not alter high-density lipoprotein cholesterol levels.

A new cholesterol-lowering agent, surfomer (AOMA), has been developed that blocks cholesterol absorption and lowers plasma cholesterol in animals. To evaluate AOMA in man, we studied its effects on plasma cholesterol, cholesterol absorption, fecal excretion of cholesterol and its bacterial degradation products, coprostanol and coprostanone, and percent saturation of gallbladder bile with cholesterol in 20 individuals chosen for hyperlipidemia. These patients had low density lipoprotein cholesterol (LDL-C) of 215 +/- 29 mg/dl. Two dose levels of AOMA were compared (10.8 and 5.4 grams daily), each for 1 mo in a study that combined features of inpatient and outpatient investigation. AOMA was tolerated well by all volunteers. There was a statistically significant correlation between percent absorption and LDL-C in both the control and AOMA treated states. AOMA lowered mean plasma cholesterol and LDL-C by 9.1% and 12.9% at the high dose and by 6.4% and 8.3% at the low dose, respectively. Triglyceride (control = 223 +/- 58 mg/dl, treatment = 232 +/- 85 mg/dl), high density lipoprotein cholesterol (HDL-C: control = 50 +/- 11 mg/dl, treatment = 50 +/- 13 mg/dl), and other lipoprotein lipids were not affected. AOMA lowered cholesterol absorption by 25% on the high dose. For 18/20 patients there was a statistically significant (p less than 0.001) correlation (r = 0.74) between percent LDL-C reduction and percent absorption inhibition. For these patients, presumably, variable effectiveness of the agent in inhibiting absorption was the most important predictor of individual responsiveness although individual variation in other cholesterol regulatory mechanisms also played a role. Two other patients showed marked LDL-C reduction at unusually low levels of absorption inhibition. We also had the opportunity to compare the effects of AOMA with neomycin in 8 volunteers. Neomycin was 50% more effective in lowering LDL-C than AOMA; however, it was twice as effective in inhibition absorption as well. AOMA dramatically reduced fecal excretion of cholesterol bacterial conversion products; whereas cholesterol per se accounted for only 50% of total neutral steroid excretion in the control state, it accounted for 93% of steroid excretion when patients were administered 10.8 grams of AOMA daily. In four patients studied there was no adverse effect of AOMA on gallbladder saturation with cholesterol; in fact, the percent saturation tended to decrease with AOMA in these four patients.

Biliary lipid classes (bile acids, phospholipids, cholesterol) as well as individual biliary bile acids were measured in duodenal bile samples obtained before treatment from 284 white men and 264 white women participating in the National Cooperative Gallstone Study. The patients had radiolucent gallstones present in visualizing gallbladders. Calculated biliary cholesterol saturation was significantly higher in women (143 +/- 43, mean +/- SD, vs. 132 +/- 39 for men). Chenodeoxycholic acid was the major biliary bile acid in both sexes (40.0 +/- 9.9 in men; 38.8 +/- 9.3 in women, NS). Cholic acid was the second most common bile acid, constituting 32.9 +/- 8.8 in men and 31.8 +/- 8.9 in women (NS). When other demographic and clinical characteristics, including serum lipids, were related with biliary lipid composition, only percent ideal body weight correlated significantly. The partial correlation coefficient adjusted for percent ideal body weight indicated that the proportion of chenodeoxycholic acid correlated negatively with the mole fraction of cholesterol in bile in men, but not in women. Multiple regression analyses showed that bile saturation could not be predicted reliably from any clinical, chemical, or radiologic measurement in either sex. Published data for biliary lipid composition in individuals with biliary disease showed considerable overlap with the National Cooperative Gallstone Study data reported here, suggesting that cholesterol gallstone disease is not caused solely by increased biliary cholesterol saturation.

This report describes a 46-yr-old man with normocholesterolemic tendon xanthomatosis. He had severe bilateral xanthomas of Achilles tendons and small lesions on patellar tendons; biopsy of the latter revealed a fibroxanthoma of high cholesterol content. He did not have clinical evidence of atherosclerotic disease. The patient's total cholesterol (TC) and triglycerides (TG) were 245 and 258 mg/dl, respectively. LDL-TC was 168 mg/dl and HDL-TC was 32 mg/dl. VLDL consisted mainly of small particles (SfO 20-100) which were unusually rich in apolipoproteins B and E (and low in apo Cs). Plasma LDL-apo B was not increased (85-120 mg/dl), but VLDL-apo B was distinctly elevated (58 mg/dl). The synthesis rate of apoLDL (29.9 mg/kg/d) was increased markedly compared to a matched control (13.9 mg/kg/d) and to a patient with familial hypercholestrolemia (15.9 mg/kg/d). The concentration of apoLDL in our patient was not increased; this was because of an associated high FCR (0.484 day-1). His HDL was relatively low in TC but high in TG, which caused an increase in HDL2b. The patient's xanthomata may have been the result of an overproduction of apo B possibly combined with a defect in HDL metabolism.

Six male subjects were fed taurine 0.5 g six times daily for 2 wk to determine the effect of a shift in bile acid conjugation pattern upon bile acid metabolism. Duodenal bile acids were analyzed, and bile acid pool size, daily fecal excretion, and biliary excretion rate were quantified. In addition, daily biliary excretion rate of cholesterol and phospholipid were quantified, and biliary saturation with cholesterol was estimated. The dose of taurine caused reversal of the bile acid glycine-to-taurine conjugation ratio. Total bile acid pool size decreased, as did the pool size of chenodeoxycholic acid. Pool sizes of cholic and deoxycholic acids did not change. Daily fecal bile acid excretion decreased slightly. Biliary secretion rates of cholesterol, phospholipid, and bile acids did not change, nor did biliary cholesterol saturation. Pool size can decrease because of increased bile acid catabolism or decreased synthesis. The fact that bile acid excretion failed to increase, and actually decreased slightly, suggests that the effect is upon bile acid synthesis. In normal humans, the effect is small and probably physiologically unimportant. In special cases, however, such as during ursodeoxycholic acid therapy, the effect of shifting conjugation pattern may become important.

Synthesis of cholesterol was measured in a familial hypercholesterolemia homozygote on four occasions from age 1.1 to 9.9 years by the sterol balance technique. Both the fecal neutral steroid and fecal bile acid components of sterol balance were elevated initially. Over the decade of study, neutral steroid excretion/kg declined 61% whereas bile acid excretion/kg was unchanged. Chronic plasmapheresis therapy every two weeks for 3.4 years reduced plasma low-density lipoprotein cholesterol 54% but had little effect on the rate of cholesterol biosynthesis.

A 29-year-old man is described who has reduced concentrations of low density lipoprotein (LDL)-cholesterol seemingly due to an unusual variant of hypobetalipoproteinemia. The patient developed retinitis pigmentosa at age 14. When studied at age 28, his total cholesterol was 104 mg/dL, triglycerides 58 mg/dL, LDL-cholesterol 44 mg/dL, and HDL-cholesterol 51 mg/dL. Lipid and lipoprotein levels of his parents and sister were normal. His excretion of bile acids (13.9 mg/kg/d) was markedly elevated at about three times normal, although absorption rates of cholesterol and bile acids appeared to be in the normal range. His high excretion of bile acids equates to a threefold increase in bile acid synthesis. Isotope kinetic studies of his lipoproteins produced unexpected findings. Total production of VLDL-apolipoprotein B (apo B) was estimated to be 20.8 mg/kg/d, which was in the normal range. Synthesis of VLDL-triglycerides was also normal at 12.0 mg/kg/h. However, 75% of VLDL-apo B was removed directly from the circulation, which was much higher than values for direct removal of VLDL-apo B in control subjects. His production rate of LDL-protein (5.2 mg/kg/d) consequently was below normal, although his fractional catabolic rate for LDL (0.40 pools/d) was not distinctly elevated. These data suggest that the patient's hypobetalipoproteinemia was due to increased direct removal of VLDL remnants and not to reduced synthesis of VLDL-apo B; this abnormality may have been the result of enhanced activity of LDL receptors, which in turn was secondary to increased synthesis of bile acids.

Cerebrotendinous xanthomatosis (CTX) is a rare disorder characterized by a defect in conversion of cholesterol into bile acids, increased plasma levels of cholestanol, and accumulations of sterols in tendons, brain, and coronary arteries. Despite the presence of tendon xanthomas, patients with CTX frequently have low levels of plasma cholesterol and low density lipoproteins (LDL). The mechanisms for a low LDL are not understood. The present study, therefore, was carried out to examine the metabolism of LDL in a 58-year-old black man with CTX. This particular patient had an LDL-cholesterol in the mid-normal range (149 +/- 6 mg/dL). Nonetheless, his fractional catabolic rate (FCR) for LDL-apolipoprotein (apo-LDL) was 0.45 pools/d, which was increased compared to 15 aged-matched men (FCR, 0.30 +/- 0.01 pools/d). His production rate for apo-LDL (18.5 mg/kg-d) also was increased compared to those of middle-aged men (13.5 +/- 2.5 mg/kg-d). Since the underlying defect in CTX can be reversed by administration of chenodeoxycholic acid (chenodiol), the patient was treated with chenodiol (250 mg 4X daily), and measurements of LDL kinetics were repeated. During chenodiol therapy, his LDL-cholesterol concentration rose significantly to 165 +/- 12 mg/dL; his FCR for apo-LDL fell to 0.29 pools/d; and his production rate of apo-LDL declined to 14.4 mg/kg-d. We postulate that chenodiol suppressed the excessive synthesis of cholesterol and bile acids, which had two effects. It curtailed both the overproduction of LDL and the excessive synthesis of LDL receptors, the latter being responsible for the high FCR of apo-LDL in the untreated state.

An increase in plasma very low density lipoprotein-triglycerides (VLDL-TG) is seen frequently during treatment with bile acid-binding resins. The purpose of this study was to determine whether this increment in VLDL-TG is due mainly to an increase in synthesis of VLDL, or to an enhanced catabolism. Three types of patients were studied: (1) 7 normotriglyceridemic subjects. (2) 4 obese patients, and (3) 9 hypertriglyceridemic patients. Before treatment they underwent a study of VLDL-TG kinetics that employed multicompartmental analysis of specific activity curves following injection of 3H-glycerol. The patients were then treated with a bile acid-binding resin, either cholestyramine or colestipol, for several weeks to several months. At the end of the treatment period, they were readmitted to the hospital for a second study of VLDL-TG kinetics. The patients showed a variable response to resin therapy. Many had an increase in concentrations of VLDL-TG, but others had no change or even a slight decrease. However, analysis of the data showed a high correlation between change in production rates of VLDL-TG and change in concentration. Also, when the data for the 20 patients were combined, there was a statistically significant increase in both synthetic rates and concentrations of VLDL-TG; in contrast, the fractional catabolic rate (FCR) was unchanged by therapy. Therefore, our data show that when treatment with bile acid sequestrants causes an increase in plasma VLDL-TG, the increase is due to an increment in production and not to a decrease in catabolism.

A method has been developed for measurement of fractional clearance rates of chylomicrons in man. The technique employs constant infusion of emulsified fat into the duodenum at a rate of 200 mg/kh/hr. After 5 hr of infusion, concentrations of triglycerides (TG) in the chylomicron fraction become constant for the subsequent 5 hr. Since the input of chylomicron-TG is known, fractional removal rates can be calculated from steady-state plasma levels. In 21 patients with normal TG levels, clearance rates for chylomicrons were extremely rapid (t1/2 for chylomicron-TG equals 4.5 +/- 2.9 (SD) min). In 30 patients with endogenous hypertriglyceridemia, clearance was generally prolonged (t1/2 equals 23 +/- 5.5 min). This delay in chylomicron clearance could have been due either to a defect in removal of all TG-rich lipoproteinarticles; a generalized defect in clearance capacity for plasma TG was apparently ruled out for most patients by the further observation that reduction of endogenous TG by caloric restriction caused chylomicron removal to return to normal. These studies also showed that endogenous-TG is removed much less efficiently than chylomicron-TG, and in some patients, this discrepancy is particularly marked.

One of the potential complications of bile acid therapy for gallstone disease is the promotion of intestinal absorption of cholesterol, thereby increasing the influx of cholesterol in body pools. To determine whether bile acid feeding is associated with an increased absorption of intestinal cholesterol, absorption measurements were made in 8 obese subjects given chenodeoxycholic acid (CCDA) or Bilron (750 mg/day). The bile acids were given in random order, separated by control periods, in patients undergoing weight reduction. Absorption of cholesterol (mass and percent) and of bile acids were determined by a technique of combined measurements of biliary lipid secretion and fecal steroid excretion. Our data showed that during treatment with either bile acid, a marked increase in pool size and hepatic secretion of bile acids occurred. However, despite an increased flux of bile acids through the intestinal tract, there was no significant increase in cholesterol absorption as compared to control periods. Absorption rates during administration of the two bile acids were approximately the same. Furthermore, plasma cholesterol concentrations were stable throughout both control and treatment periods. Bile acid absorption remained highly efficient (greater than 96%) during all periods, even with administration of exogenous bile acids.

To better define the mechanisms by which chenodeoxycholic acid (CDCA) alters the lipid composition of bile and promotes dissolution of cholesterol gallstones, we have studied the effects of relatively low doses of CDCA on the metabolism of biliary lipids in 10 subjects without gallstones. In 5 subjects, the effects of CDCA feeding were compared to those of cholic acid, a bile acid that apparently does not dissolve cholesterol stones. The following measurements were carried out during control and treatment periods: (1) composition of biliary lipids, (2) hepatic secretion rates of biliary lipids, (3) pool sizes of bile acids, and (4) specific composition of bile acids. Low doses of CDCA consistently reduced the lithogenicity of gallbladder bile by decreasing the proportion of cholesterol relative to the solubilizing lipids--bile acids and lecithin. This decrease in lithogenicity was associated with a selective reduction in hepatic secretion rates of cholesterol. At the doses of CDCA given, secretion rates of bile acids and lecithin and pool sizes of bile acids were not significantly changed; also conversion of cholesterol into bile acids was not completely inhibited. Cholic acid feeding appeared to increase the total size of the bile acid pool, but it did not affect the lithogenicity of bile or secretion rates of cholesterol. The data show that at low doses CDCA lowers lithogenicity of bile by reducing hepatic secretion of cholesterol, while cholic acid does not have a similar effect.

Six male subjects with normal gastroenterologic function were studied to determine the effects of ursodeoxycholic (15 mg/kg X day) and tauroursodeoxycholic (20 mg/kg X day) acid feeding on bile acid synthesis and cholesterol absorption. Each bile acid was fed for 1 mo and withheld for the next month. Subjects remained on a metabolic ward and consumed a constant diet of 500 mg of cholesterol mixed with solid and liquid formulas. Before the study started, each subject received 50 muCi of [4-14C]cholesterol intravenously. During the study, stools were collected for the determination of 24-h fecal acidic and neutral sterol excretion, and blood was drawn twice weekly for determination of serum cholesterol specific activity. At the end of each month an intestinal perfusion study was performed to measure total bile acid pool size and hourly biliary secretion rates of cholesterol, phospholipid, and bile acid. From these data, the percentage of cholesterol absorption and total endogenous bile acid synthesis could be calculated. Neither ursodeoxycholic nor tauroursodeoxycholic acid feeding decreased endogenous bile acid synthesis. During bile acid feeding periods, the percentage of cholesterol absorption was decreased.

To evaluate the effectiveness of colestipol and clofibrate in patients with hypercholesterolemia and normal concentrations of triglycerides, 27 patients were randomized into three groups, and colestipol, clofibrate, and avicel powder placebo were compared for effects on concentration of total plasma lipid and lipoprotein cholesterol and triglyceride in a single blind protocol over 8 mo. Mean pretreatment values for low density lipoprotein (LDL)-cholesterol and very low density lipoprotein (VLDL) triglyceride were 250 mg/dl and 68 mg/dl, respectively. Colestipol (30 g/day) lowered total- and LDL-cholesterol by 25% and 31%k, respectively, while VLDL-triglyceride rose. Overall clofibrate lowered total- and LDL-cholesterol by 13% and 12% while lowering VLDL-triglyceride 21% and VLDL cholesterol by 50%. For clofibrate, certain patients showed a more pronounced effect than others: in seven of nine patients clofibrate lowered both mean total- and LDL-cholesterol by 17% (range 8% to 31%) and 19% (range 10%--44%) respectively, whereas two patients did not respond to clofibrate. High density lipoproteins were not affected by either colestipol or clofibrate in these patients. Thus, while colestipol was more consistently effective, certain hypercholesterolemic patients responded equally well to clofibrate with substantial lowering of total-, LDL-, and VLDL-cholesterol.

In this report, kinetic studies of plasma very low-density lipoprotein-triglyceride (VLDL-TG) were examined in five brothers (three affected and two unaffected) from a family with primary hypertriglyceridemia. Synthesis and catabolism of VLDL-TG were studied by in vivo labelling of plasma TG with 3H-glycerol, and multicompartmental analysis of the plasma die-away curves. Results of the kinetic studies revealed the following information: (1) one brother, who had the highest plasma TG level and was obese, had both overproduction and a reduced fractional catabolic rate (FCR) of VLDL-TG; (2) second brother, who had moderate hypertriglyceridemia, had a low FCR and high-normal synthesis of VLDL-TG; (3) a third, who had only mildly elevated TG, had a low FCR and normal synthesis of VLDL-TG; and (4) the two normolipidemic brothers had neither overproduction nor decreased FCR of VLDL-TG. The composition of the soluble apoproteins of VLDL was normal. The apoprotein E phenotypes were E4/3 in four brothers, and E3/2 in the fifth. We have reached the following conclusions regarding this family: (1) the common kinetic abnormality of VLDL-TG metabolism in the hypertriglyceridemic brothers was a low clearance of VLDL-TG; (2) impaired catabolism of VLDL could not be explained by the apoprotein C or E patterns; and (3) the most severe hypertriglyceridemia occurred when the decreased FCR was present in conjunction with VLDL-TG overproduction due to obesity. Thus, a moderate defect in catabolism of plasma TG appears to be responsible for one familial form of primary hypertriglyceridemia.

Type 3 hyperlipoproteinemia (HLP) results from the accumulation in plasma of remnants of very low density lipoproteins (VLDL) due to a defect in apolipoprotein E. Current data suggest that VLDL remnants can be removed by the same receptors that remove low density lipoproteins (LDL). Mevinolin has been shown to enhance clearance of LDL by LDL receptors. In this study, mevinolin markedly lowered both VLDL remnants and LDL in a patient with type 3 HLP, presumably by increasing the activity of LDL receptors.

Obese subjects are prone to supersaturated bile, which is maintained or increased during weight loss. In this report, two related studies were carried out on obese subjects to investigate effects of bile acid feeding on biliary lipid metabolism before and during weight reduction. In one study, chenodeoxycholic acid (CDCA), 750 mg/day, was given to 12 obese subjects during weight maintenance (1st mo) and during weight reduction (2nd mo). In the second study, effects of two bile acid preparations, CDCA and Bilron (containing mostly cholic acid and deoxycholic acid), randomly administered, were compared in another 12 obese subjects undergoing weight reduction. The results show that obese subjects had large pools of bile acids during weight maintenance which decreased on caloric restriction (1,000 kcal/day). CDCA increased pool size only modestly during weight maintenance, from 3,536 +/- 1,267 (SD) mg to 4,735 +/- 1,434 mg. Both CDCA and Bilron markedly reexpanded the contracted pool of bile acids in obese subjects on weight reduction. However, significantly reduced saturation of bile occurred only in those on CDCA and weight reductions, whereas supersaturation was unaltered when weight was maintained constant in these patients, or when Bilron was given. No significant side effects were noted during bile acid feeding for any of the subjects. Thus, CDCA given to obese subjects on weight reduction will reduce bile saturation and could protect against gallstones.

We examined the effect of diabetic control on very low-density lipoprotein-triglyceride (VLDL-TG) metabolism in six patients with type II (noninsulin-dependent) diabetes mellitus and marked hypertriglyceridemia. VLDL-TG transport was determined using 3H-glycerol as an endogenous precursor of VLDL-TG, and the resultant kinetic data were evaluated by multicompartmental analysis. Studies were performed in the hypertriglyceridemic diabetic subjects during poor diabetic control and again after 3 months of diabetic treatment, and the results were compared to studies in nondiabetic normolipidemic subjects and nondiabetic subjects with familial forms of hypertriglyceridemia. In the poorly controlled diabetics, mean VLDL-TG synthesis was threefold higher than in the normolipidemic subjects, and the mean fractional catabolic rate (FCR) of VLDL-TG was only one-third of the normals. With diabetic treatment, plasma triglyceride levels fell by more than 50%, but remained fourfold higher than the normals. This was associated with a decrease in mean VLDL-TG synthesis to a level similar to that observed in the genetic hyperlipidemic subjects, but still 2.6-fold higher than the normals. In addition, the mean FCR rose after diabetic control to a level slightly above that of the genetic hyperlipidemic subjects, but remained less than one-half of the normal value. However, the response of VLDL-TG kinetics to diabetic treatment was not uniform. In four subjects, control of hyperglycemia ameliorated the hypertriglyceridemia primarily by decreasing VLDL-TG overproduction. In the other two subjects, diabetic treatment had a greater effect on the FCR than an overproduction of VLDL-TG. Thus, in this select group of diabetic, hypertriglyceridemic subjects, poor diabetic control contributed to both VLDL-TG overproduction and low FCRs. Failure of diabetic treatment to restore VLDL-TG kinetic parameters to normal suggests that the hypertriglyceridemia was due not only to diabetes mellitus but also to an additional abnormality affecting lipoprotein metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

We have selected for this study a well-defined group of patients with moderately advanced but compensated alcoholic cirrhosis. They were well-nourished and had no ascites, varices, azotemia, or encephalopathy. Liver biopsy showed little or no necrosis and inflammation despite wide-spread fibrosis. Serum bilirubin, transaminase, alkaline phosphatase, albumin and globulins were essentially normal. Biochemical evidence for liver disease was restricted to modest elevation of BSP retention, gamma GTP, serum bile acid concentrations, and urinary bile acid excretion. Except for changes in the interrelationships among the three biliary lipids, they were generally spared the abnormalities of sterol metabolism described in other patients with more advanced, more active liver disease. Thus, striking abnormalities in the metabolism of cholesterol and bile acids probably require severe reductions in functioning hepatocellular mass, major portal-systemic shunting, high disease activity, or all three to become manifest.

The metabolisms of VLDL, IDL, and LDL and their interconversions have been studied in ten obese untreated male Pima Indian diabetics compared to 16 age-, sex-, and weight-matched nondiabetics. VLDL was elevated in the diabetics and had abnormal composition, as indicated by a significantly higher ratio of triglyceride/apo B. Fractional catabolic rates for both VLDL apoB and VLDL triglyceride were lower in diabetics, and diabetics had increased production of VLDL triglyceride but not VLDL apoB compared to obese nondiabetics. A higher proportion of VLDL apoB was removed without conversion to LDL in diabetics. LDL cholesterol and apoB were higher in diabetics, but production of LDL apoB was not different from nondiabetics. Fractional catabolic rate for LDL apoB, however, was significantly lower in the diabetics. The data indicate that the triglyceride-rich VLDL in non-insulin-dependent diabetics are less readily converted to LDL, whereas the elevated LDL in this group of diabetics is due to impaired clearance. Thus, decreased conversion of VLDL to LDL and impaired LDL clearance are two opposing phenomena which may influence the LDL concentration of diabetics in either direction. Thus, despite minimal changes in LDL concentration, there are multiple defects in the metabolism of LDL in non-insulin dependent diabetes which may contribute to the increased atherogenesis in this disorder.

This report describes a patient with advanced planar xanthomatosis and benign monoclonal gammopathy who had normal plasma concentrations of cholesterol and triglycerides (TG). Decreased electrophoretic mobilities of very low density lipoprotein (VLDL), intermediate density lipoproteins (IDL) and chylomicrons were found. No changes in electrophoretic mobility were found for low density lipoprotein (LDL) and high density lipoproteins (HDL). The patient's disease was associated with a progressive decline in plasma-TG and VLDL-TG over a 2 yr period. He also appeared to develop an increased rate of clearance of VLDL-TG and chylomicrons. These changes in the metabolism of TG-containing lipoproteins were unaccompanied by alterations in the synthesis of either cholesterol or bile acids. The observations in this patient led us to the conclusion that his normal to low levels of VLDL-TG could be explained by both enhanced tissue uptake and increased lipolysis of VLDL-TG. The most likely explanation for these findings is that the patient had immune complexes between his TG-rich lipoproteins and an abnormal monoclonal gamma globulin. This patient is another example of an expanding group of subjects in whom xanthomatosis can develop without hyperlipidemia.

The relationship between bile acid turnover and plasma triglyceride metabolism was examined in a group of seven moderately overweight and hypertriglyceridemic men. Bile acid synthesis was stimulated by the continuous aspiration of duodenal contents so that 150% of the bile acid pool was removed in 18 hr. In comparison with the average concentration of very low density lipoprotein triglyceride (VLDL-TG) during a preceding 8-10 hr control period, bile withdrawal led to an increase in VLDL-TG of 34%, 43%, 32%, 14%, 26%, 14%, and 8% (mean +24%) in the seven men. In control studies performed on another day the mean change over a similar period of time, but without bile withdrawal, was +1% (p less than 0.01). The kinetics of VLDL triglyceride were studied in some of the subjects by analyzing the triglyceride specific radioactivity curves following injections of radiolabelled glycerol. In control studies of 26 hr duration the curves were resolved into two apparent exponential functions, the second part of the curve appearing between 15 and 18 hr after pulse-labeling. During bile withdrawal, the second apparent exponential developed sooner, within 4 hr of beginning the aspiration and coincided with the rise in triglyceride concentration. The fractional rate of the second exponential was at least as fast during bile withdrawal as during the control period despite the increase in VLDL-TG pool size, suggesting that the turnover of triglyceride was higher at a time when bile acid production was being stimulated.