Biomedical subjects

S J Robins

Publications and source records attributed to S J Robins.

At least 37 records · Page 2Linked to original sources

PubMed1995

Distribution of lipids in 8,500 men with coronary artery disease. Department of Veterans Affairs HDL Intervention Trial Study Group.

In the present study we measured fasting lipid profiles in over 8,500 community-living men with coronary artery disease (CAD) to determine the distribution of lipid abnormalities in this population: 81% were white and 16% black; mean age 62.9 +/- 8 years; mean total cholesterol 214 +/- 41 mg/dl; low-density lipoprotein (LDL) cholesterol 140 +/- 37 mg/dl; high-density lipoprotein (HDL) cholesterol 39 +/- 11 mg/dl; and triglycerides 190 +/- 142 mg/dl. After adjusting for age, the only significant difference between blacks and whites was a higher HDL cholesterol in blacks (45 vs 38 mg/dl, p < 0.003). With use of cut points established by the National Cholesterol Education Program, 87% of subjects had high LDL cholesterol (> or = 100 mg/dl), 38% had low HDL cholesterol (< 35 mg/dl), and 33% had high triglycerides (> 200 mg/dl). We estimated that 42% of men with CAD would be definite candidates for cholesterol-lowering medication according to the National Cholesterol Education Program guidelines and that 41% of those in whom cholesterol-lowering medication would not be definitely indicated had low levels of HDL cholesterol. We conclude that (1) black men with CAD have substantially higher HDL cholesterol than white men, (2) almost 90% of male patients with CAD are candidates for dietary intervention and > 40% may need medications to lower LDL cholesterol, and (3) 40% of patients without a definite indication for cholesterol-lowering medications have low levels of HDL cholesterol.

Adult↗

PubMed1995

Studies on the mechanism of the ursodeoxycholic acid-induced increase in hepatic low-density lipoprotein binding.

Previously, we have shown, in golden Syrian hamsters, that chronic feeding of ursodeoxycholic acid (UDCA), in contrast to that of its 7 alpha-epimer, chenodeoxycholic acid (CDCA), produced a significant increment in hepatic low-density lipoprotein (LDL) uptake, despite similar suppression of bile acid synthesis by both bile acids. Evidence for a direct effect of this bile acid on hepatic LDL metabolism was shown in vitro, with isolated hamster hepatocytes, suggesting that this effect was unique to UDCA and specific for receptor-mediated LDL catabolism. The aim of the present study was to define the cellular mechanism(s) associated with this phenomenon, using male golden Syrian hamsters. Regardless of chronic exposure of the liver to either UDCA or CDCA, acute incubation with UDCA consistently resulted in an increase of LDL binding to isolated hepatocytes by 15 to 40%. Furthermore, chronic treatment with either UDCA or CDCA did not result in alterations in lipoprotein particle composition. Likewise, incubation of hepatocytes with UDCA was not associated with a change of the membrane lipid composition. In isolated liver membrane fractions, UDCA increased both the maximum number of LDL binding sites and the affinity constant for LDL by around 35%, suggesting an interaction of UDCA with the LDL receptor, at the plasma membrane level, independent of an effect on receptor cycling. The results of the studies support a role for UDCA in the recruitment of cryptic LDL receptors from a cellular membrane pool, possibly due to the unique localization of UDCA in the plasma membrane lipid bilayer.

Animals↗

PubMed1995

Gender differences in the development of hyperlipemia and atherosclerosis in hybrid hamsters.

In response to a diet enriched in saturated fat and cholesterol (CH), male Syrian hamsters develop hyperlipemia and changes of early atherosclerosis. However, it has not been determined if female hamsters are equally susceptible to an atherogenic diet. Male and female hamsters of the F1B hybrid strain (Bio Breeders, Fitchburg, MA) were fed either a chow diet or this diet (HiFat) with added saturated fat (10% coconut oil) and CH (0.05%) for up to 12 weeks. Female hamsters ate significantly more than males, and with the HiFat diet gained threefold more weight than males. However, with the HiFat diet, serum triglycerides (TGs) and CH were markedly increased only in male hamsters. Furthermore, only in males was there a significant increase in stainable fat in the aorta that corresponded to an increase in subintimal foam cells. In freely feeding males, the largest percentage increase in serum CH was in the TG-rich fraction of lipoproteins. After females were castrated, serum TG and CH levels increased to the same extent as in males. These studies demonstrate a profound gender difference in response to an atherogenic diet in these hamsters that has parallels to the lipid patterns of humans and their susceptibility to atherosclerosis.

Animals↗

PubMed1995

Dietary monounsaturated and polyunsaturated fatty acids are comparable in their effects on hepatic apolipoprotein mRNA abundance and liver lipid concentrations when substituted for saturated fatty acids in cynomolgus monkeys.

Although studies have shown that saturated and polyunsaturated fats can mediate plasma lipid and apolipoprotein (apo) concentrations at the mRNA level, there is little data on the role of monounsaturated fats. We determined hepatic lipid and apo mRNA levels in 10 cynomolgus monkeys fed three diets that provided 30% of energy as fat with 0.1% cholesterol by weight and differed solely by the substitution of saturated, mono- and polyunsaturated fats as 60% of total fat energy. Total, LDL, and HDL cholesterol, as well as LDL apo B, HDL apo A-I and HDL total apo C concentrations, were reduced with the mono- and polyunsaturated fat diets relative to the saturated fat diet. Although fat saturation did not significantly affect hepatic apo A-I, B, C-II, or E mRNA abundance, hepatic apo C-III mRNA concentrations were uniformly lower (-23%, P < 0.01) with the mono- and polyunsaturated fat diets than with the saturated fat diet. Interestingly, liver triglycerides were significantly elevated with the monounsaturated fat diet relative to the saturated fat diet, but no other differences in hepatic lipids were noted among diets. Hepatic triglyceride composition was shown to reflect dietary fatty acid composition, with liver triglycerides enriched in myristic and palmitic fatty acids during the saturated fat diet, oleic acid during the monounsaturated fat diet and linoleic acid during the polyunsaturated fat diet. We conclude that dietary monounsaturated fats are comparable to polyunsaturated fats in their effects on hepatic lipid and apo mRNA levels in this species, with both unsaturated fats significantly reducing only hepatic apo C-III mRNA abundance relative to saturated fat.

Animals↗

PubMed1995

Diurnal changes and adaptation by the liver of hamsters to an atherogenic diet.

Studies were performed in freely feeding, male (F1B) Syrian hamsters fed a high-fat diet to determine the extent and manner of adaptation of the liver to diurnal changes in eating patterns and an increase in serum lipids. Serum cholesterol and triglycerides strongly paralleled changes in food consumption and were 40-50% greater during the 12-h dark period than the 12-h light period of the diurnal cycle. Hepatic cholesterol changes closely approximated changes in serum cholesterol (r = 0.916) due principally to changes in hepatic cholesteryl esters that were on average about 10-fold greater with the high-fat diet than with a chow diet. With the high-fat diet, hepatic cholesteryl esters were, however, extremely variable and were 40% greater at the mid-dark than at the mid-light period. With high fat there was also a marked increase in the secretion of very low density lipoproteins (VLDL) from the liver that were cholesteryl ester rich and closely paralleled the diurnal changes in hepatic cholesteryl esters (r = 0.911). In contrast, although with a high-fat diet biliary cholesterol secretion was increased, the increase in cholesterol in bile exhibited no diurnal pattern and with the high-fat diet was far less in magnitude than the increase of cholesterol in VLDL. Biliary cholesterol secretion is dependent on bile acid secretion. However, with the high-fat diet, neither the bile acid pool size nor bile acid secretion was increased compared with chow-fed controls. Moreover, with high fat at mid-dark period, bile acid secretion was significantly less than controls at mid-dark period. Thus in these hamsters a high-fat diet produced a marked increase in serum cholesterol that was distinctly diurnal and was compensated for by a diurnal increase in hepatic cholesteryl ester stores and the secretion of cholesteryl esters in VLDL. In contrast, cholesterol secretion in bile did not correspond to the fluctuating changes of cholesterol in the liver and was far less in magnitude than would be necessary to reduce a greatly expanded pool of hepatic cholesterol.

Adaptation, Physiological↗

PubMed1995

Red blood cell membrane phosphatidylethanolamine fatty acid content in various forms of retinitis pigmentosa.

In order to test the hypothesis that retinitis pigmentosa (RP) is associated with fatty acid abnormalities within cell membrane phospholipids, red blood cell membrane (RBC) phosphatidylethanolamine (PE) fatty acid content (% of total fatty acids) was measured using high performance liquid chromatography and capillary column gas chromatography in 155 patients from separate families with different genetic types of RP and 101 normal subjects. After controlling for the effects of age and sex, patients with all genetic forms of RP had significantly (P < 0.001) reduced mean RBC PE 22:6 omega 3 (n-3) (docosahexaenoic acid, DHA) content, and significantly (P < 0.001) elevated mean RBC PE dimethyl acetal (DMA) forms of 16:0, 18:0, and 18:1 omega 9 (n-9) as compared with normal subjects. RBC PE content of 22:5 omega 3 (n-3) (a precursor to DHA) and 18:2 omega 6 (n-6) (the major dietary essential fatty acid) were not significantly different in RP than in controls. Analysis by genetic types of RP showed that the mean RBC PE DHA percentages were significantly reduced by 24%, 14%, 30%, and 17%, respectively, in dominant, recessive, X-linked, and isolate forms of RP. The relative amounts of plasmalogens as indicated by DMA forms of 16:0 and 18:0 were significantly (P < 0.01) increased in dominant (by 33% and 25%), recessive (by 36% and 25%), and isolate cases (by 32% and 26%) of RP as compared with normal subjects. No such differences were seen in X-linked cases versus controls. Our data indicate that RBC PE DHA content is decreased in all genetic types of RP patients as compared to control subjects, and that RBC PE plasmalogens are increased in dominant, recessive, and isolate forms of RP. These data raise the possibility that membrane phospholipid fatty acid abnormalities may contribute to the pathogenesis of RP.

Acetals↗

PubMed1994

Phosphatidylcholine protects against fibrosis and cirrhosis in the baboon.

BACKGROUND/AIMS: Polyunsaturated soybean lecithin (55%-60% phosphatidylcholine [PC]) protects against fibrosis in alcohol-fed baboons. The present study was undertaken to determine whether PC is the active agent. METHODS: Virtually pure PC (equivalent to that contained in the lecithin) was administered for up to 6.5 years with or without alcohol, and the results were compared with those of unsupplemented groups. RESULTS: Control livers remained normal, whereas 10 of 12 baboons fed alcohol without PC developed septal fibrosis or cirrhosis with transformation of 81% +/- 3% of the hepatic lipocytes to collagen-producing transitional cells. By contrast, none of the eight animals fed alcohol with PC developed septal fibrosis or cirrhosis, and only 48% +/- 9% of their lipocytes were transformed, indicating that PC was indeed the protective compound. Ethanol feeding also resulted in decreased liver phospholipids and PC, and both were corrected by the supplementation. Furthermore, PC stimulated collagenase activity in cultured lipocytes. This PC consisted of several species, mainly dilinoleoylphosphatidylcholine (40%-52%) and palmitoyl-linoleoylphosphatidylcholine (23%-24%). Only dilinoleoylphosphatidylcholine duplicated the effect of the PC on collagenase. Other species of PC, phosphatidylethanolamine, free fatty acids, or choline were without effect. CONCLUSIONS: PC prevents alcohol-induced fibrosis and cirrhosis in nonhuman primates, and dilinoleoylphosphatidylcholine appears to be the active species, possibly by promoting collagen breakdown.

Animals↗

PubMed1994

Hepatic phosphatidylethanolamine methyltransferase activity is decreased by ethanol and increased by phosphatidylcholine.

UNLABELLED: Phosphatidylethanolamine N-methyltransferase participates in the synthesis of membrane phosphatidylcholine. Its activity was reported to be decreased in patients with alcoholic cirrhosis, but it is not known whether this is a consequence of the cirrhosis or precedes it. This question was studied in a baboon model of alcohol-induced fibrosis. Phosphatidylethanolamine N-methyltransferase activity was measured in sequential percutaneous needle liver biopsies by the conversion of phosphatidylethanolamine to phosphatidylcholine, using radioactive S-adenosylmethionine as a methyl donor. Chronic alcohol consumption (1-6 years) significantly decreased hepatic phospholipid and phosphatidylcholine levels and reduced phosphatidyl-ethanolamine N-methyltransferase activity even before the development of fibrosis. These effects were prevented or attenuated by supplementing the diet with 2.8 g/1000 kcal of a preparation rich in dilinoleoyl phosphatidylcholine, a highly bioavailable phosphatidylcholine species. There were significant (p < 0.001) correlations between phosphatidylethanolamine N-methyltransferase activity and both hepatic phosphatidylcholine (r = 0.678) and total phospholipid (r = 0.662). CONCLUSIONS: 1. Alcohol consumption diminishes phosphatidylethanolamine N-methyltransferase activity prior to the development of cirrhosis and decreases the hepatic content of its product, namely phosphatidylcholine, a key component of cell membranes. This may promote hepatic injury and possibly trigger fibrosis. 2. Phosphatidylcholine administration ameliorates the ethanol-induced decrease in phosphatidylethanolamine N-methyltransferase activity and corrects phospholipid and phosphatidylcholine depletions, thereby possibly contributing to the protection against alcoholic liver injury.

Animals↗

PubMed1994

Evidence that hepatic triglycerides provide acylglycerides for synthesis of bile phosphatidylcholines.

To determine the biochemical origin of bile phosphatidylcholines (PCs), rat liver perfusions with 16:1 fatty acid (FA) and [3H]glycerol were performed to generate novel radiolabeled bile and liver PCs and their hepatic glyceride precursors. Results showed total equilibration of bile and liver 16:1-16:1 PC when the specific activity of precursor glycerol-3-phosphate was kept constant. However, when the specific activity of glycerol-3-phosphate decreased during the labeling period and during a prolonged chase period with 17:1 FA and nonradiolabeled glycerol, the specific activity of bile 16:1-16:1 PC was appreciably higher than this same PC in the liver and during the chase period was even higher than its hepatic 16:1-16:1 acylglycerol precursors, phosphatidic acid and diglyceride. During the chase period with 17:1 FA, new radiolabeled 16:1-17:1 PC was formed, and again the specific activity of this PC in bile was greater than this PC and 16:1-17:1 phosphatidic acid and diglyceride in the liver. Only the specific activity of liver 16:1-16:1-(FA) triglyceride equaled or was high enough to support the formation of new bile 16:1-16:1 PC. These studies indicate that bile PCs do not directly derive from preexisting hepatic PCs or by de novo synthesis through phosphatidic acids and diglycerides, but likely originate by remodeling from a pool of hepatic triglycerides.

Animals↗

PubMed1994

Modification of the dextran-Mg2+ high-density lipoprotein cholesterol precipitation method for use with previously frozen plasma.

Although dextran-Mg2+ precipitation produces accurate and precise results for high-density lipoprotein (HDL) cholesterol in fresh plasma and serum, precipitation of frozen specimens with triglycerides > 2.26 mmol/L (> 200 mg/dL) is difficult. We developed a modification that dilutes thawed samples by 35% and increases dextran-Mg2+ reagent to 15% of sample volume. Standard precipitations were performed on 62 fresh EDTA-treated plasma specimens; supernatant solutions were analyzed fresh and after freezing. Standard and modified methods were also performed on thawed, paired plasmas. In specimens with triglycerides < or = 2.26 mmol/L, HDL cholesterol results for all methods were similar. For triglycerides > 2.26 mmol/L, however, bias and precision were significantly affected by freezing, and 38.5% of samples with standard precipitation required additional procedures to produce clear supernatant solutions. HDL cholesterol concentrations for thawed samples with standard precipitation were significantly greater than for fresh samples (P < 0.02), but those for the modified method were not different from fresh samples, and only one specimen required additional steps to produce a clear supernate.

Chemical Precipitation↗

PubMed1994

Hepatic phosphatidylcholines: evidence for synthesis in the rat by extensive reutilization of endogenous acylglycerides.

Studies were performed to compare the extent of fatty acid incorporation into liver phosphatidylcholines (PCs) by acyl remodeling and by de novo synthesis. To this end, isolated rat livers were first perfused with palmitoleic acid (16:1) and [2-3H]glycerol and then with 17:1 fatty acid and nonradiolabeled glycerol that resulted in the formation of new molecular species of radiolabeled PCs containing 16:1 and 17:1 acyl groups. The specific activities of newly formed molecular species of the de novo precursors of acylglyceride synthesis, phosphatidic acids (PAs) and diglycerides (DGs), and the products of synthesis, PCs and triglycerides (TGs), were measured at periods during both the labeling period of perfusion with 16:1 (first 15 min) and the more prolonged chase period with 17:1 (up to 120 min). At the end of the labeling period, the specific activity of all the 16:1-containing PAs, DGs, and 16:1-16:1-16:1 and 16:1-16:1-18:2 TGs were the same and were much higher than any molecular species that did not contain 16:1. The specific activities of these molecular species are indicative of the specific activity of molecular species synthesized exclusively by de novo synthesis (i.e., by acylation of glycerol 3-phosphate) during the labeling period. In contrast, the specific activity of 16:1-16:1 PC was only 2/3 that of the other 16:1-16:1 glycerides, and the specific activities of the other 16:1-containing PCs were only about 1/3 that of the corresponding 16:1-containing PAs, DGs, and 16:1-16:1 TGs. After the labeling period and during the chase period with perfusion of 17:1 and nonradiolabeled glycerol, the specific activities of major 16:1 PCs exceeded the specific activities of their corresponding PAs and DGs and remained considerably higher than these precursors of de novo synthesis for the duration of perfusions. However, during this period, the specific activities of major 16:1 PCs were less than their corresponding molecular species of TGs. During the chase period, new 17:1 molecular species of PCs were formed that were also radiolabeled. The specific activity of 16:1-17:1 PC, the 17:1 PC with the highest specific activity, always exceeded its corresponding PA and DG precursors. During the chase period, non-16:1 and non-17:1 molecular species of PCs that comprised the bulk of hepatic PCs were also radiolabeled and the specific activities of these molecular species progressively increased during this period.(ABSTRACT TRUNCATED AT 400 WORDS)

Acylation↗

PubMed1993

Rationale and design of the Department of Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (HIT) for secondary prevention of coronary artery disease in men with low high-density lipoprotein cholesterol and desirable low-density lipoprotein cholesterol.

Although a large body of epidemiologic evidence suggests that low levels of high-density lipoprotein (HDL) cholesterol are strongly associated with an increased risk of coronary artery disease (CAD), no large-scale clinical trials focusing on this association have been reported. This report describes the rationale and design of the Department of Veterans Affairs HDL Intervention Trial (HIT), a multicenter, randomized, controlled clinical trial designed to determine whether lipid therapy reduces the combined incidence of CAD death and nonfatal myocardial infarction in men with established CAD who have low levels of HDL cholesterol with "desirable" levels of low-density lipoprotein (LDL) cholesterol. Twenty-five hundred men with CAD and HDL cholesterol < or = 40 mg/dl, LDL cholesterol < or = 140 mg/dl, and triglycerides < or = 300 mg/dl are being recruited at 20 Department of Veterans Affairs medical centers, randomized to either gemfibrozil or placebo, and followed in a double-blind manner for an average of 6 years. In this population, gemfibrozil is expected to increase HDL cholesterol by 10 to 15%, have a negligible effect on LDL cholesterol, and lower triglycerides by 30 to 40%. Because an estimated 20 to 30% of patients with CAD have a low HDL cholesterol as their primary lipid abnormality, the results of this trial are expected to have far-reaching clinical implications.

Adult↗

PubMed1993

Hepatic cholesterol synthesis and the secretion of newly synthesized cholesterol in bile.

To determine the effect of increased hepatic cholesterol synthesis on the secretion of newly synthesized cholesterol in bile, rats were fed with cholestyramine, a bile-acid-binding resin that increases the number of hepatocytes that synthesize cholesterol. Cholesterol synthesis was measured 15 min after [3H]water injection to avoid appreciable exchange between the liver and serum of newly synthesized cholesterol that accumulates in the serum in studies of several hours duration. At 15 min after [3H]water injection, the specific radioactivity of cholesterol in the liver and hepatic microsomes was greatly increased in resin-fed animals compared with controls. However, with resin, the specific radioactivity of newly synthesized cholesterol that was secreted in bile was the same as for controls. At 15 min after [3H]water injection the specific radioactivity of serum cholesterol was minimally increased and not different in resin and control groups. In contrast, in studies that were longer than 60 min, newly synthesized cholesterol in serum was appreciably increased in resin-fed animals, and newly synthesized cholesterol in bile was also greatly increased compared with controls. Thus, when appreciable cholesterol exchange is avoided, an increase in hepatic cholesterol synthesis and the number of hepatocytes that synthesized cholesterol does not result in an increase in newly synthesized cholesterol in bile. Our results suggest that newly synthesized cholesterol is secreted in bile from a fixed subpopulation of hepatocytes. From a comparison of the specific radioactivity of newly synthesized cholesterol in whole liver and bile, it can be estimated that this subpopulation of hepatocytes represents about 20% of the total hepatocyte mass.

Animals↗

PubMed1993

Changes in biliary lipid secretion during normal development and diurnal cycling in the rat.

Biliary lipid secretion in conjunction with hepatic cholesterol synthesis was determined in normal male rats at 4, 5, 7, and 9 weeks of age, during a period of linear growth and a near fourfold increase in liver size. Studies were performed both at periods of low (mid-light cycle) and high (mid-dark cycle) hepatic cholesterol synthesis. Biliary bile salt, phospholipid, and cholesterol secretion (per g of liver) markedly decreased with an increase in liver size. Whereas the secretion of bile salts and phospholipid was not significantly different in mid-dark and mid-light periods for animals of the same age, cholesterol secretion was greater in the mid-dark than in the mid-light period at 5, 7, and 9 weeks of age. Relationships between biliary cholesterol secretion and bile salt and phospholipid secretion differed at mid-dark and mid-light periods, as follows: cholesterol secretion was not significantly related to bile salt secretion at mid-dark (r = 0.49, P > 0.05) but was related at mid-light (r = 0.73, P = 0.003); and although cholesterol secretion was significantly related to phospholipid secretion at mid-dark, this relationship was not nearly as strong as at mid-light (P < 0.005, comparing r = 0.95 at mid-light with r = 0.53 at mid-dark). In contrast, at mid-dark, biliary cholesterol secretion was strongly related to hepatic cholesterol synthesis (r = 0.84, P < 0.0001) whereas at mid-light the two were not significantly related (r = 0.13, P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1993

Effect of phosphatidylcholine molecular species on the uptake of HDL triglycerides and cholesteryl esters by the liver.

It has previously been shown that the hydrolysis of high density lipoprotein (HDL) phospholipids by hepatic lipase promotes the hepatic uptake of triglyceride and cholesteryl ester from HDL. Since the hydrolysis of HDL phospholipids promotes HDL cholesteryl ester uptake, then it is possible that the hepatic metabolism of HDL could be altered by changing the molecular species composition of HDL phosphatidylcholine (PC) (the major phospholipid in HDL). To test this possibility the uptake of [3H]triolein and [14C]cholesteryl oleate by the isolated perfused rat liver was determined in a nonrecirculating perfusion system following a bolus injection of reconstituted HDL (rHDL) prepared with rat serum HDL apolipoproteins, [3H]triolein, [14C]cholesteryl oleate, unesterified cholesterol, and one of five molecular species of phosphatidylcholine (16:0-18:2, 16:1-16:1, 18:0-18:2, 18:1-16:0, or 20:1-20:1), 18:1-16:0 phosphatidylcholine diether, or the total phosphatidylcholine fraction isolated from rat serum HDL. The apolipoprotein profiles and lipid compositions of all the rHDL were similar. The greatest uptake of [3H]triolein was obtained with the rHDL prepared with 16:0-18:2 phosphatidylcholine. The amount of [3H]triolein taken up by the liver when the rHDL were prepared with 16:1-16:1, 18:0-18:2, 18:1-16:0, 20:1-20:1, 18:1-16:0 phosphatidylcholine diether, or rat serum HDL phosphatidylcholine was 56.7%, 51.7, 39.9%, 27.6%, 31.8%, and 84.7%, respectively, of the amount taken up from the rHDL prepared with 16:0-18:2 phosphatidylcholine. Likewise, the greatest amount of [14C]cholesteryl oleate was taken up by the liver when the rHDL was prepared with 16:0-18:2 phosphatidylcholine and the variation in [14C]cholesteryl oleate uptake from the various rHDL displayed a pattern of dependence on the phosphatidylcholine molecular species of rHDL similar to triolein uptake. The variation in the rate of rHDL phosphatidylcholine hydrolysis by hepatic lipase in vitro as a function of the PC molecular species composition of the rHDL also resembled the variation in the hepatic uptake of [14C]cholesteryl oleate and [3H]triolein. Partial substitution of rHDL phosphatidylcholine with the minor phospholipids isolated from rat serum HDL affected neither the hepatic uptake of [3H]triolein or [14C]cholesteryl oleate nor phosphatidylcholine hydrolysis by hepatic lipase in vitro when 16:0-18:2 phosphatidylcholine or rat serum HDL phosphatidylcholine was used to prepare the rHDL. On the other hand, when rHDL was prepared with 20:1-20:1 phosphatidylcholine, the inclusion of the minor phospholipids increased [3H]triolein and [14C]cholesteryl oleate uptake and phosphatidylcholine hydrolysis approximately twofold.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Effect of reduction of plasma triglycerides with gemfibrozil on high-density-lipoprotein-cholesterol concentrations.

The aim of this study was to test the hypothesis that the plasma triglyceride (TG) concentration must be reduced below approximately 0.85-1.13 mmol l-1 (75-100 mg/dl-1) in order to achieve a substantial increase in plasma high-density-lipoprotein-cholesterol (HDL-C) levels. The study design consisted of a non-randomized clinical trial, which was conducted at an out-patient clinic at a university-affiliated VA Medical Center. The participants consisted of 55 ambulatory middle-aged men with a baseline fasting HDL-C concentration of less than or equal to 1.17 mmol l-1 (45 mg dl-1) and baseline TG in the range 1.13-5.6 mmol l-1 (100-500 mg dl-1). Subjects were treated with gemfibrozil, 600 mg twice a day for 3 months. Fasting plasma HDL-C, TG, low density lipoprotein-cholesterol, and total cholesterol were measured at 1-month intervals for 3 months. Subjects were divided into three groups on the basis of TG level achieved on therapy: Group I (n = 14), TG less than 0.85 mmol l-1 (75 mg dl-1); Group II (n = 20), TG 0.86-1.41 mmol l-1 (76-125 mg dl-1); Group III (n = 21), TG greater than 1.41 mmol l-1 (125 mg dl-1). The mean increase in HDL-C in Group I was 0.20 mmol l-1 (7.8 mg dl-1), a significantly (P = 0.0067) greater increase than was observed in the other two groups. There was no correlation between the magnitude of change in TG and the magnitude of change in HDL-C concentration in the group as a whole (Pearson's correlation coefficient, r = -0.06, P = 0.6). In conclusion, the increase in HDL-C levels observed with gemfibrozil therapy is associated with the absolute level of TG achieved by therapy. Substantial increases in HDL-C concentration might not be expected to occur consistently unless TG levels are reduced to values that are considered below the usually cited 'normal' range.

Cholesterol, HDL↗

PubMed1992

Metabolism of high density lipoprotein lipids by the rat liver: evidence for participation of hepatic lipase in the uptake of cholesteryl ester.

In order to determine the role of hepatic lipase in the hepatic uptake and metabolism of high density lipoprotein (HDL) triglycerides, cholesteryl esters, and phospholipids, isolated rat livers were perfused with a reconstituted HDL (rHDL) radiolabeled with [3H]triolein and [14C]cholesteryl oleate or palmitoyl-[14C]linoleoyl phosphatidylcholine. A bolus of radiolabeled rHDL was injected into the portal vein and livers were perfused for 5 min using a nonrecirculating perfusion system. Recovery of rHDL triolein in the liver as intact triolein was used to determine the amount of unmetabolized rHDL remaining in the liver. After correcting for the amount of unmetabolized rHDL remaining in the liver, about 30% of the rHDL triolein was hydrolyzed of which 19% was recovered in the liver and 11% in the perfusate. Moreover, about 7% of the rHDL phosphatidylcholine was hydrolyzed to lysophosphatidylcholine, all of which was recovered in the perfusate. Although there was no hydrolysis of rHDL cholesteryl oleate, about 30% of the cholesteryl oleate was taken up by the liver. Preperfusion of the liver with heparin to deplete the liver of hepatic lipase resulted in about a 70% reduction in rHDL triolein hydrolysis and about a 75% reduction in rHDL cholesteryl oleate uptake. Although hepatic lipase hydrolyzes both triglycerides and phosphatidylcholines, elimination of the triolein from rHDL had no effect on the uptake of rHDL cholesteryl oleate, but replacement of the rHDL phosphatidylcholine with a nonhydrolyzable phosphatidylcholine diether resulted in an 87% reduction in cholesteryl oleate uptake. These results indicate that hepatic lipase is necessary for the hepatic uptake of both HDL triglycerides and cholesteryl esters and that the uptake of cholesteryl esters is not dependent on the hydrolysis of HDL triglycerides but is dependent on the hydrolysis of HDL phospholipids.

Animals↗

PubMed1991

Utilization of different fatty acids for hepatic and biliary phosphatidylcholine formation and the effect of changes in phosphatidylcholine molecular species on biliary lipid secretion.

Biliary cholesterol secretion is ordinarily tightly coupled to phosphatidylcholine (PC) secretion. Bile PCs are distinct in composition and predominantly composed of molecular species with 16:0 in the sn-1 position and 18:2 and 18:1 in the sn-2 position. In an attempt to acutely change the composition of biliary PCs and to assess the effect of a change in PCs on biliary cholesterol secretion, isolated livers were perfused with a variety of single free fatty acids. Rat livers with bile duct cannulas were perfused with a recirculating medium, taurocholate (40 mumol/h), and albumin-bound 16:1, 17:1, 18:1, 20:1, 18:2, 20:4, or 20:5 fatty acids (90 mumol/h) for 2 h. Biliary lipid secretion was measured and bile and liver PC compositions were compared at the start and end of perfusion. Results showed 1) greater utilization of shorter chain than longer chain fatty acids for bile PC formation (16:1 greater than 17:1 greater than 18:2 or 18:1 greater than 20:5, 20:4 or 20:1); 2) no similar pattern of FA utilization for liver PC formation; 3) preferentially greater incorporation of fatty acids into bile PCs compared to liver PCs when perfused fatty acids were used for esterification at both sn-1 and sn-2 positions of PC (to form diunsaturated PCs); and 4) increased biliary secretion of cholesterol relative to PC only when the population of PCs that was newly formed included more hydrophilic molecular species of PC than are present in native bile (that was observed only with perfusion of 16:1). Changes in biliary PC secretion or cholesterol/PC secretion occurred independently of any change in bile salt secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗