Effects of feeding fish oil on the properties of lipoproteins isolated from rhesus monkeys consuming an atherogenic diet

This study examined plasma lipids and lipoproteins of rhesus monkeys fed fish oil incorporated into a highly atherogenic diet containing saturated fat and cholesterol. The animals were fed diets containing 2% cholesterol and either 25% coconut oil (group I), 25% fish oil/coconut oil (1:1; group II), or 25% fish oil/coconut oil (3:1; group III) for 12 months (n = 8/group). Adding menhaden fish oil to the diet increased plasma eicosapentaenoic acid and docosahexaenoic acid and decreased plasma linoleic acid in animals fed the fish oil containing diets. Plasma concentrations of all lipoprotein fractions were decreased in the fish oil groups. VLDL isolated from group I animals exhibited beta-mobility on agarose gels but the VLDL from groups II and III animals did not. The group I VLDL was more highly enriched in cholesteryl ester than was VLDL from groups II and III. Group I LDL had a small but significant increase in cholesteryl ester content compared to group III LDL. No differences in HDL composition were observed in the 3 groups. At least 6 times less apo E was recovered in VLDL, IDL, and LDL from group III animals than from group I animals. Assuming 1 molecule of apo B per lipoprotein particle, there were 50% fewer VLDL, IDL, and LDL particles in group III than in group I animals. Group III also had significantly lower molar ratios of apo E/apo B in VLDL, IDL, and LDL than did group I animals. When VLDL from all 3 groups were incubated with J774 macrophages at equal protein concentrations, only the VLDL from the group I animals stimulated cholesterol esterification. Thus, introducing fish oil into an atherogenic diet reduced the number of VLDL, IDL and LDL particles in plasma by as much as 50%, reduced the cholesteryl ester content of the circulating lipoprotein, and reduced the ability of the VLDL to stimulate cholesterol esterification in macrophages.     

Accelerated turnover of very low density lipoprotein triglycerides in chronic alcohol users. A possible mechanism for the up-regulation of high density lipoprotein by ethanol

The concentration of high density lipoproteins (HDL) is related to the catabolism of triglyceride-rich lipoproteins. In order to elucidate the mechanisms by which alcohol increases plasma HDL levels we measured the turnover kinetics of very low density lipoprotein (VLDL) triglycerides in 10 alcoholic men without liver disease and in nonalcoholic control men matched for age, weight and plasma VLDL triglyceride level. The study was repeated in the alcoholics after a 2-week abstinence period. The alcoholic men had elevated HDL cholesterol but reduced low density lipoprotein (LDL) cholesterol as compared to the controls. The fractional catabolic rate and the total turnover (production) rate of VLDL triglycerides were both significantly increased (P less than 0.05) in the alcoholic men before abstinence. After withdrawal of alcohol both the synthetic rate and the catabolic rate of VLDL triglycerides returned to normal and the HDL (HDL2 and HDL3) cholesterol fell. The per cent decrease in HDL2 cholesterol during abstinence was positively correlated to the respective fall of VLDL triglyceride fractional catabolic rate (r = +0.51). The results suggest that the absence of hypertriglyceridemia and the elevated levels of HDL in regular alcohol users may be partly based on increased metabolic clearance of VLDL particles and on subsequent accelerated transfer of the VLDL surface components to HDL.     

Changes in plasma lipoprotein concentrations and compositions upon feeding cholesterol in high- and low-responding rhesus monkeys

When fed cholesterol, the high-responding rhesus monkeys develop severe hypercholesterolemia, whereas low-responding rhesus monkeys show only slight increases in plasma cholesterol levels. We report changes in plasma lipoprotein concentrations and compositions along with changes in plasma lipid concentrations in high- and low-responding rhesus monkeys fed a high-cholesterol diet. On low-cholesterol diet, the concentrations and compositions of plasma lipoprotein fractions were similar in the two groups. Upon feeding cholesterol, plasma very-low-density (VLDL), intermediate-density (IDL) and low-density (LDL)-lipoprotein concentrations increased in both groups, but the increases were significantly (p less than 0.01) higher in high-responders than in low-responders. Plasma HDL concentration decreased significantly (p less than 0.01) in high responders but not in low responders. In high responders, percent cholesterol increased in both VLDL and IDL fractions but in low responders, it decreased in VLDL and increased in IDL. Percent triglycerides decreased in VLDL, IDL and LDL fractions in high responders, while in low responders it tended to increase in VLDL, remained unchanged in IDL and decreased in LDL. The composition of HDL did not change in the two groups upon feeding cholesterol. Thus, when fed cholesterol, the high- and the low-responding monkeys respond distinctly differently in plasma lipoprotein concentrations and compositions. The responses occurred simultaneously, suggesting metabolic interrelationships between various lipoproteins.     

Purpurogallin in the prevention of hypercholesterolemic atherosclerosis

Effects of purpurogallin (PPG), an antioxidant on high cholesterol diet-induced atherosclerosis, and changes in blood lipid profile and lipid peroxidation product malondialdehyde (MDA), aortic tissue MDA, chemiluminescence (M-CL), a marker for antioxidant reserve and antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-P_x)] were investigated in rabbits. The rabbits were divided into three groups: Group I, regular rabbit chow; Group II, same as Group I+cholesterol (1%); and Group III, same as Group II+PPG (14 mg/kg, orally, daily). Serum concentrations of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), and blood MDA were measured before and after 4 and 10 weeks on the respective diets. The aorta was removed at the end of 10 weeks for assessment of atherosclerotic changes, MDA concentration, M-CL, and antioxidant enzymes. Coronary arteries were also examined for atherosclerotic changes. Serum TC, LDL-C, and LDL-C/HDL-C ratio increased whereas HDL-C decreased in Group II and their values were similar in Groups II and III. Aortic tissue MDA, M-CL, CAT, and GSH-P_x activity increased in Group II but these values in Group III were lower than in Group II except for MDA which was greater in Group III than in Group II. Atherosclerotic changes were greater in Group II than in Group III. Histological changes were similar in Groups II and III. Atherosclerotic changes were also observed in the coronary arteries of Groups II and III, however, they were less in Group III than in Group II. Increased levels of aortic MDA and decreased levels of antioxidant reserve, which were associated with the development of atherosclerosis, suggest a role for oxygen radicals in the pathogenesis of hypercholesterolemic atherosclerosis. The protection afforded by PPG, which was associated with reversal of the antioxidant reserve to control level, in spite of hypercholesterolemia, supports the hypothesis that oxygen radicals are involved in the development of hypercholesterolemic atherosclerosis. These results suggest that PPG retard the development of hypercholesterolemic atherosclerosis because of its antioxidant activity without lowering blood cholesterol level.     

Effects of Chinese herbal drug, dai-saiko-to on plasma lipids, lipoproteins and liver lipid contents in guinea pig

Effects of Chinese herbal drug, Dai-saiko-to, on plasma lipids, lipoproteins and liver lipid contents were investigated in guinea pig with/without cholesterol feeding. Guinea pigs were divided into 4 groups (Group 1: normal chow (N) diet, Group 2: N + 1% Dai-saiko-to (D) diet, Group 3: 1% cholesterol (C) diet, Group 4: 1% C+ 1% D diet), and were treated for 5 weeks. Significant body weight reductions were observed in Groups 3 and 4 compared to Groups 1 and 2. Significant reductions of plasma triglyceride (TG) and very low and low density lipoproteins [(V) LDL]-TG were found in Group 3 compared to Groups 1, 2, and 4. (HDL)-TG significantly decreased in Groups 3 and 4 compared to Groups 1 and 2, but no significant difference was noted between Groups 1 and 2, and Groups 3 and 4. Liver lipid contents analysis showed no significant changes between Groups 1 and 2, and Groups 3 and 4, respectively, but the distribution of lipid droplets as pathologically determined using a computer program showed Group 4 had less lipid deposition compared to Group 3. These data suggest that Dai-saiko-to acts on triglyceride metabolism in hypercholesterolemic guinea pigs.     

Novel and traditional cardiovascular risk factors in children after Kawasaki disease: implications for premature atherosclerosis

OBJECTIVES: We determined the profile of cardiovascular risk factors in children late after Kawasaki disease (KD) and compared it with that of age-matched healthy children. BACKGROUND: Concerns have been raised regarding the possibility of a predisposition of KD to premature atherosclerosis later in life. METHODS: A cohort of 102 subjects were studied: 37 KD patients with coronary aneurysms (group I), 29 KD patients with normal coronary arteries (group II), and 36 healthy age-matched children (group III). The fasting total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein (apo) A-I, apoB, and homocysteine levels were compared among the three groups. In addition, blood pressure and brachioradial arterial stiffness, as determined by pulse wave velocity (PWV), were measured and compared. RESULTS: Group I subjects had lower HDL cholesterol (p = 0.016) and apoA-I levels (p = 0.044) and higher apoB levels (p = 0.029) and PWV (p = 0.001) than group III control subjects. Likewise, the apoB levels (p = 0.007) and PWV (p = 0.042) were higher in group II than in III subjects, although their HDL cholesterol (p = 0.54) and apoA-I (p = 0.52) levels were similar. The LDL cholesterol levels were higher in group I and II patients than in controls, although not statistically significant (p = 0.17). Blood pressure and homocysteine levels did not differ among the groups. CONCLUSIONS: An adverse cardiovascular risk profile, as characterized by a proatherogenic alteration of the lipid profile and increased arterial stiffness, occurs in children after KD. The profile is worse in those with than in those without coronary aneurysms.     

Type III hyperlipoproteinemia: rise in high-density lipoprotein levels in response to therapy.

The experience of the Washington University Lipid Research Center in the treatment of type III hyperlipoproteinemia is reported. Six women and seven men were prescribed a type III diet and/or clofibrate over periods of two to eight months. Mean total plasma cholesterol and triglyceride levels declined by 51 and 74 per cent, respectively, whereas mean levels of high-density lipoprotein (HDL) cholesterol rose from 34 to 50 mg/dl (p < 0.001). Rises in HDL cholesterol levels were seen in every subject, whereas levels of HDL triglycerides fell. Plasma concentrations of apolipoproteins (Apo) A-I and A-II, which make up 90 per cent of the protein moieties of the HDL, were also measured for the first time in the patients with type III hyperlipoproteinemia by radioimmunoassay. Levels of both apoproteins rose with therapy (from 83 to 108 mg/dl and from 35 to 43 mg/dl, respectively, p < 0.02 for both). The sums of triglyceride + cholesterol in the HDL, + A-I + A-II in plasma, were increased by therapy from 170 to 211 mg/dl (p < 0.05). There was a significant negative correlation between the change in HDL cholesterol and the change in very low-density lipoprotein (VLDL) triglyceride (r = ? 0.720; p < 0.01). Low-density lipoprotein (LDL) (density (d) 1.006 to 1.063 g/ml) cholesterol remained unchanged but LDL triglycerides decreased. Therefore, both the levels and compositions of the low- and high-density lipoproteins were affected by therapy. Levels of cholesterol and triglycerides in the d < 1.006 g/ml lipoproteins both decreased but without changes in their ratios. Visible regression of xanthomas occurred in six of six patients. Intermittent claudication and angina pectoris diminished in five of five and two of two patients, respectively. Thus, alterations in plasma lipoproteins were associated with clinical improvement. It is not known which of the changes in lipoproteins were most beneficial—the lowering of the d < 1.006 class, which is directly related to high coronary risk, or the elevation of high-density lipoproteins, which are inversely related to risk. Perhaps both contributed to the unique responsiveness of clinical signs and symptoms to therapy in patients with type III hyperlipoproteinemia.     

Role of circulating high-density lipoprotein and triglycerides in coronary artery disease: risk and prevention

A substantial body of evidence suggests that circulating levels of high-density lipoprotein (HDL) and certain triglyceride-carrying lipoproteins may, like low-density lipoprotein (LDL), be important risk factors in the development of atherosclerotic coronary artery disease (CAD). Furthermore, both low HDL cholesterol and high triglyceride levels are frequently associated with other CAD risk factors, whose correction, often by hygienic means, may reduce CAD risk without fear of adverse side effects. However, the available evidence is not yet sufficiently coherent and compelling to justify guidelines (analogous to those for LDL cholesterol) for specific pharmacologic treatment of low plasma HDL cholesterol or moderately elevated plasma triglyceride levels to prevent CAD.     

Administration of hydrogen-saturated saline decreases plasma low-density lipoprotein cholesterol levels and improves high-density lipoprotein function in high-fat diet-fed hamsters

Hydrogen (dihydrogen; H(2)) has an antiatherosclerotic effect in apolipoprotein (apo) E knockout mice. The goals of this study were to further characterize the effects of H(2) on the content, composition, and biological activities of plasma lipoproteins in golden hamsters. Plasma analysis by enzymatic method and fast protein liquid chromatography showed that 4-week intraperitoneal injection of hydrogen-saturated saline remarkably decreased plasma total cholesterol and low-density lipoprotein (LDL) cholesterol levels in high-fat diet-fed hamsters. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis of apolipoproteins from ultracentrifugally isolated plasma lipoproteins revealed a marked decrease of apo B100 and apo B48 in LDL. A profound decrease of apo E level in very low-density lipoprotein was also observed. Besides, we determined the functional quality of high-density lipoprotein (HDL) particles isolated from H(2)-treated and control mice. H(2) significantly improved HDL functionality assessed in 2 independent ways, namely, (1) stimulation of cholesterol efflux from macrophage foam cells by measuring HDL-induced [(3)H]cholesterol efflux and (2) protection against LDL oxidation as a measure of Cu(2+)-induced thiobarbituric acid reactive substances formation. Administration of hydrogen-saturated saline decreases plasma LDL cholesterol and apo B levels and improves hyperlipidemia-injured HDL functions, including the capacity of enhancing cellular cholesterol efflux and playing antioxidative properties, in high-fat diet-fed hamsters.     

Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers

The bile acid analogue obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist in development for treatment of several chronic liver diseases. FXR activation regulates lipoprotein homeostasis. The effects of OCA on cholesterol and lipoprotein metabolism in healthy individuals were assessed. Two phase I studies were conducted to evaluate the effects of repeated oral doses of 5, 10 or 25 mg OCA on lipid variables after 14 or 20 days of consecutive administration in 68 healthy adults. Changes in HDL and LDL cholesterol levels were examined, in addition to nuclear magnetic resonance analysis of particle sizes and sub‐fraction concentrations. OCA elicited changes in circulating cholesterol and particle size of LDL and HDL. OCA decreased HDL cholesterol and increased LDL cholesterol, independently of dose. HDL particle concentrations declined as a result of a reduction in medium and small HDL. Total LDL particle concentrations increased because of an increase in large LDL particles. Changes in lipoprotein metabolism attributable to OCA in healthy individuals were found to be consistent with previously reported changes in patients receiving OCA with non‐alcoholic fatty liver disease or non‐alcoholic steatohepatitis.     

High-density lipoprotein cholesterol as an indicator of liver function and prognosis in noncholestatic cirrhotics.

BACKGROUND AND AIMS: The liver plays a central role in production and degradation of lipoproteins. Declining lipoprotein cholesterol may reflect deteriorating liver function. METHODS: We reviewed the records of 248 veterans with noncholestatic cirrhosis followed in our clinics or referred for liver transplantation between January 1, 1997 and October 31, 2002 (analysis period) and confirmed our findings prospectively in 165 noncholestatic cirrhotic veterans newly referred for liver transplantation between November 1, 2002 and May 1, 2004 (validation period). RESULTS: In the analysis group, albumin, bilirubin, INR, and Model for End-Stage Liver Disease (MELD) score correlated strongly with high-density lipoprotein (HDL) cholesterol, weakly but significantly with total cholesterol and very-low-density lipoprotein cholesterol (VLDL), and poorly with low-density lipoprotein cholesterol (LDL). Transplant-free mortality at 90, 180, and 365 days was 17/201 (8.5%), 19/173 (11.0%), and 38/119 (31.9%), respectively. Death at all 3 time points was associated with significantly lower initial levels of HDL, VLDL, and total cholesterol, but not LDL cholesterol. Of the lipoproteins, HDL was the best predictor of survival at 180 and 365 days (concordance statistics .86+/-.05 and .78+/-.05, respectively). By multivariate logistic regression, HDL cholesterol and MELD score were independent predictors of survival at 6 and 12 months. By Cox regression, HDL cholesterol below 30 mg/dL was associated with 3.4-fold increase in the hazard ratio for cirrhotic death. In the validation period, HDL cholesterol was confirmed to be significantly associated with death or transplantation at 6 or 12 months. CONCLUSIONS: HDL cholesterol in noncholestatic cirrhotic patients is a liver function test and an indicator of prognosis.     

Differences in apolipoproteins and low-density lipoprotein subfractions in postmenopausal women on and off estrogen therapy: results from the Framingham Offspring Study

The use of estrogens by postmenopausal women has been associated with reduced risk of coronary artery disease (CAD) in some studies, possibly due to favorable effects of estrogens on plasma lipoproteins. In order to examine such effects, we studied 180 postmenopausal women from the Framingham Offspring Study, selected by type of menopause (natural or oophorectopic) and estrogen use. We determined fasting plasma total cholesterol, triglyceride, very-low-density lipoprotein (VLDL) cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and apolipoprotein (apo) A-l and B concentrations, as well as LDL particle size (LDL 1 to LDL 6). Apo A-l levels were significantly (P less than .005) higher, and diastolic blood pressure and glucose levels were significantly (P less than .05) lower in postmenopausal women taking estrogen regardless of type of menopause. HDL cholesterol levels were also higher in women taking oral estrogens, but differences were significant only for the oophorectomized group (P less than .02). Total cholesterol, VLDL cholesterol, and LDL cholesterol levels were significantly lower (P less than .01) in women with natural menopause who were taking estrogens than in women with natural menopause not taking this medication. No significant differences between estrogen users and nonusers were found with regard to triglyceride levels or LDL particle score, in either the natural menopause or oophorectomy groups. These data indicate that estrogen use in postmenopausal women is associated with significantly elevated plasma apo A-l levels and decreased LDL cholesterol concentrations.     

Influence of plasma triglycerides on lipoprotein patterns in normal subjects and in patients with coronary artery disease

This study examined the correlation of plasma triglyceride levels with concentrations of intermediate, low and high density lipoproteins (IDL, LDL, and HDL, respectively) and to particle sizes of LDL in 93 normal men and 106 men with coronary artery disease. Plasma triglyceride concentrations were in the normal range for all persons in both groups. Analysis of lipoproteins of density less than 1.063 g/ml was carried out by analytical ultracentrifugation. The analytical pattern gave the peak Sf for LDL as well as an indication of heterogeneity of particle sizes in the density range of LDL. In both normal subjects and patients with coronary artery disease, a positive correlation was found between peak Sf for LDL and concentrations of plasma triglycerides. Plasma triglyceride levels also were correlated positively with concentrations of Sf 20 to 60 lipoproteins and total IDL mass, and inversely with HDL cholesterol levels. Furthermore, the value for peak Sf for LDL correlated inversely with the IDL mass concentration and IDL/LDL mass ratio, and positively with the HDL cholesterol levels. The results indicate that the lipoprotein pattern, including lipoprotein concentrations and particle sizes, is sensitive to concentrations of plasma triglycerides even when the latter are within the normal range.     

Thyroid disease and lipids.

The composition and the transport of lipoproteins are seriously disturbed in thyroid diseases. Overt hypothyroidism is characterized by hypercholesterolaemia and a marked increase in low-density lipoproteins (LDL) and apolipoprotein B (apo A) because of a decreased fractional clearance of LDL by a reduced number of LDL receptors in the liver. The high-density lipoprotein (HDL) levels are normal or even elevated in severe hypothyroidism because of decreased activity of cholesteryl-ester transfer protein (CETP) and hepatic lipase (HL), which are enzymes regulated by thyroid hormones. The low activity of CETP, and more specifically of HL, results in reduced transport of cholesteryl esters from HDL(2) to very low-density lipoproteins (VLDL) and intermediate low-density lipoprotein (IDL), and reduced transport of HDL(2) to HDL(3). Moreover, hypothyroidism increases the oxidation of plasma cholesterol mainly because of an altered pattern of binding and to the increased levels of cholesterol, which presents a substrate for the oxidative stress. Cardiac oxygen consumption is reduced in hypothyroidism. This reduction is associated with increased peripheral resistance and reduced contractility. Hypothyroidism is often accompanied by diastolic hypertension that, in conjunction with the dyslipidemia, may promote atherosclerosis. However, thyroxine therapy, in a thyrotropin (TSH)-suppressive dose, usually leads to a considerable improvement of the lipid profile. The changes in lipoproteins are correlated with changes in free thyroxine (FT(4)) levels. Hyperthyroidism exhibits an enhanced excretion of cholesterol and an increased turnover of LDL resulting in a decrease of total and LDL cholesterol, whereas HDL are decreased or not affected. The action of thyroid hormone on Lp(a) lipoprotein is still debated, because both decrease or no changes have been reported. The discrepancies are mostly because of genetic polymorphism of apo(a) and to the differences between the various study groups. Subclinical hypothyroidism (SH) is associated with lipid disorders that are characterized by normal or slightly elevated total cholesterol levels, increased LDL, and lower HDL. Moreover, SH has been associated with endothelium dysfunction, aortic atherosclerosis, and myocardial infarction. Lipid disorders exhibit great individual variability. Nevertheless, they might be a link, although it has not been proved, between SH and atherosclerosis.     

Receptor binding activity of high-density lipoproteins containing apoprotein E from abetalipoproteinemic and normal neonate plasma

The receptor binding properties of lipoproteins derived from neonates and abetalipoproteinemic patients were examined. Compared to normal adults, the neonate plasma contained reduced cholesterol levels, with only 40% of the total cholesterol transported in the low-density lipoproteins (LDL). When compared at equal cholesterol concentrations, however, the total neonate lipoproteins (d less than 1.21) were as effective as adult d less than 1.21 lipoproteins in stimulating cholesteryl ester formation in cultured human fibroblasts. Analysis of the neonate lipoproteins explained their enhanced ability to deliver cholesterol to the cells via LDL (apoprotein B,E) receptors: the neonate d = 1.02-1.063 fraction contained, in addition to LDL, alpha 2-migrating, apoprotein E-rich high-density lipoproteins (HDL1), which were isolated by Geon-Pevikon electrophoresis. In binding studies performed with human fibroblasts at 4 degrees C, the neonate HDL1 were 14-fold more effective than either neonate or adult human LDL in displacing 125I-LDL from apo-B,E receptors. The neonate HDL (d = 1.063-1.21) contained a subfraction rich in apo-E and apo(E-A-II), which was isolated by heparin-Sepharose chromatography. This fraction was also active in displacing 125I-LDL from the receptors on cultured fibroblasts. Apoprotein E-containing HDL subclasses, similar to those described in the blood of neonates, were present in the d less than 1.063 and d = 1.063-1.21 lipoprotein fractions of patients with abetalipoproteinemia. These HDL with apo-E were enriched in cholesterol and were as effective as normal LDL in competing with 125I-LDL for apo-B,E receptor-mediated binding, internalization, and degradation. When incubated with cultured human fibroblasts, the HDL with apo-E from the abetalipoproteinemic subjects increased the cholesteryl ester mass three- to fourfold. These studies suggest that neonates and abetalipoproteinemic subjects may depend (at least in part) upon lipoproteins containing apo-E to deliver cholesterol to various tissues via the LDL (apo-B,E) receptor.     

Prolonged stimulation of the adrenals by corticotropin suppresses hepatic low-density lipoprotein and high-density lipoprotein receptors and increases plasma cholesterol

Pituitary ACTH has been shown to strongly stimulate adrenal receptors for low-density lipoprotein (LDL) and high-density lipoprotein (HDL) scavenger receptor class B type 1(SR-BI) to provide precursor cholesterol for glucocorticoid synthesis. The present study aimed to determine the effects of ACTH on hepatic cholesterol metabolism and plasma lipoproteins. Treatment of Sprague Dawley rats or normal C57BL/6J mice with ACTH for 3.5 d reduced hepatic SR-BI and LDL receptors. Simultaneously, cholesterol in plasma LDL and HDL was increased. None of these effects could be reproduced using glucocorticoids instead of ACTH, and they were abolished in adrenalectomized rats, indicating an obligate role of the adrenals for the effects of ACTH observed in the liver. When ACTH was given to LDL receptor-deficient mice, plasma LDL did not increase and the increase in HDL cholesterol remained, as did the suppression of hepatic SR-BI. Our data show that prolonged ACTH treatment suppresses hepatic SR-BI and LDL receptors in vivo in rodents, resulting in elevated plasma HDL and LDL. The adrenals are obligate for these effects, suggesting that ACTH releases some factor(s) that suppresses hepatic LDL and SR-BI receptors. Hypothetically, this novel mechanism would further promote channeling of cholesterol to the adrenals in situations of prolonged stress.     

Combined effect of exogenous insulin and sucrose on alterations in plasma lipoproteins induced by cholesterol feeding in the rat

We have recently reported increased cholesterol concentrations in high-density and very-low-density lipoproteins (HDL and VLDL) in sucrose-fed rats with exogenous hyperinsulinemia. In order to see if exogenous hyperinsulinemia has any effect on the alterations in plasma lipoproteins induced by cholesterol feeding, we fed a cholesterol-rich diet supplemented with lard, cholic acid and propylthiouracil to hyperinsulinemic, sucrose-supplemented rats and examined plasma lipoprotein profiles. Three control groups were investigated: one receiving chow only, the other receiving a cholesterol-rich diet, the third receiving exogenous insulin, sucrose, and no cholesterol-rich diet but chow. Hyperinsulinemia was induced by a constant s.c. infusion of porcine insulin (6 U/day) from an osmotic minipump. Insulin infusion plus sucrose produced an increase in HDL cholesterol concentrations similar to that seen in the previously reported injection model in the face of no change in total and low-density lipoprotein (LDL) cholesterol. Rats receiving a cholesterol-rich diet but no insulin developed marked hypercholesterolemia characterized by an elevation of cholesterol not only in LDL but also in intermediate-density lipoprotein (IDL) and VLDL. Infusing insulin into cholesterol-fed rats produced a further increase in IDL and VLDL cholesterol but was not accompanied by any further increase in LDL cholesterol. HDL cholesterol was decreased below normal.     

Lipolytic activities in rats fed a sucrose-rich diet supplemented with either cystine or cholesterol: relationships with lipoprotein profiles

To study the relationships between lipolytic activities and plasma lipoprotein levels in rats, three diets were given for 8 weeks: a semipurified diet (based on sucrose, casein and lard) and this diet enriched with 5% cystine or with 1% cholesterol. Both supplemented diets induced hypercholesterolemia. Lipoprotein analysis by density gradient ultracentrifugation of plasma indicated that hypercholesterolemia of cystine-fed rats (+52%) was characterized by an increased cholesterol level in high-density lipoprotein (HDL; +131%) and low-density lipoprotein 2 (LDL2; +147%), the lipoprotein fraction containing essentially apolipoprotein-E-rich high-density lipoproteins (HDL1), and was associated with a decreased cholesterol level in triglyceride-rich lipoproteins (TRL: -69%). That obtained by cholesterol feeding (+28%) was due to a large increase in the TRL cholesterol level (+315%) whereas cholesterol was reduced in HDL (-40%) and in LDL2 (-60%). Under these dietary conditions, the activity of hepatic lipase (HL) was measured in liver homogenates and those of both HL and lipoprotein lipase were measured in plasma after heparin injection. The activity of HL (1,783 +/- 132 mU/g liver in control rats) was increased by 48% in cystine-fed rats and decreased by 40% in cholesterol-fed rats. Similar changes were observed in the activity of both lipases measured in postheparin plasma. Highly significant positive correlations linked each lipolytic activity with the level of cholesterol, phospholipids and proteins in LDL2 (HDL1-rich fraction) and in HDL. In contrast, significant negative correlations were found between all of the TRL components and the activity of the lipases.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of niacin on lipoprotein subclass distribution

Dyslipidemia is a heterogeneous metabolic condition; high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very-low-density lipoprotein represent families of lipoprotein particles that differ in size and composition and vary in atherogenicity. Lipoprotein subclasses containing apolipoprotein B promote atherosclerosis, of which the most atherogenic appear to be the small, dense LDL and large very-low-density lipoprotein subclasses, while the large HDL2 subclass, which transports esterified cholesterol from the periphery to the liver, is considered the more cardioprotective. Niacin has long been known to improve concentrations of all major lipids and lipoproteins, but it also has consistently favorable effects on subclass distribution. A MEDLINE search was conducted for clinical studies reporting the effects of niacin on lipoprotein subclasses. The niacin-associated elevations in HDL cholesterol likely stem from differential drug effects on subclasses, producing favorable changes in levels of HDL2 and apolipoprotein A-I. Niacin has more moderate LDL cholesterol-lowering efficacy, but this change is associated with an increase in LDL particle size and a shift from small LDL to the less atherogenic, large LDL subclasses. In addition, it also tends to decrease concentrations of the larger very-low-density lipoprotein subclasses. Niacin confers diverse benefits with respect to both the quantity and quality of lipid and lipoprotein particles.     

Neue Entwicklungen in der Lipidtherapie

Statins are highly effective lipid modifying drugs which have been proven to be beneficial in numerous outcome studies. However, stricter low-density lipoprotein (LDL) cholesterol goals (according to European guidelines LDL cholesterol should now be below 70?mg/dl in patients at very high cardiovascular risk), intolerance to statins and the limited efficacy of statins in some genetic forms of dyslipidemia make it necessary to develop new lipid modifying drugs. Antisense oligonucleotides can reduce the production of apolipoprotein B and proprotein convertase subtilisin/kexin type 9 (PCSK9, a regulator of the LDL receptor) and thus reduce LDL cholesterol levels by 25?C70%. Microsomal triglyceride transfer protein (MTP) inhibitors interfere with the production of lipoproteins in the liver and cholesteryl ester transfer protein (CETP) inhibitors can increase high density lipoprotein (HDL) cholesterol by more than 100% and decrease LDL cholesterol by 30%. Other new approaches address apolipoprotein A1 thus stimulating reverse cholesterol transport and many of the new approaches also decrease lipoprotein (a) concentrations. Although these developments seem very promising only clinical studies will show which drugs will ultimately reach clinical application.