Plasma Very Low Density Lipoprotein Cholesterol Research Articles

ASGR1 Deficiency Inhibits Atherosclerosis in Western Diet-Fed ApoE-/- Mice by Regulating Lipoprotein Metabolism and Promoting Cholesterol Efflux.

Atherosclerosis is the most common cause of cardiovascular diseases. Clinical studies indicate that loss-of-function ASGR1 (asialoglycoprotein receptor 1) is significantly associated with lower plasma cholesterol levels and reduces cardiovascular disease risk. However, the effect of ASGR1 on atherosclerosis remains incompletely understood; whether inhibition of ASGR1 causes liver injury remains controversial. Here, we comprehensively investigated the effects and the underlying molecular mechanisms of ASGR1 deficiency and overexpression on atherosclerosis and liver injury in mice. We engineered Asgr1 knockout mice (Asgr1-/-), Asgr1 and ApoE double-knockout mice (Asgr1-/-ApoE-/-), and ASGR1-overexpressing mice on an ApoE-/- background and then fed them different diets to assess the role of ASGR1 in atherosclerosis and liver injury. After being fed a Western diet for 12 weeks, Asgr1-/-ApoE-/- mice exhibited significantly decreased atherosclerotic lesion areas in the aorta and aortic root sections, reduced plasma VLDL (very-low-density lipoprotein) cholesterol and LDL (low-density lipoprotein) cholesterol levels, decreased VLDL production, and increased fecal cholesterol contents. Conversely, ASGR1 overexpression in ApoE-/- mice increased atherosclerotic lesions in the aorta and aortic root sections, augmented plasma VLDL cholesterol and LDL cholesterol levels and VLDL production, and decreased fecal cholesterol contents. Mechanistically, ASGR1 deficiency reduced VLDL production by inhibiting the expression of MTTP (microsomal triglyceride transfer protein) and ANGPTL3 (angiopoietin-like protein 3)/ANGPTL8 (angiopoietin-like protein 8) but increasing LPL (lipoprotein lipase) activity, increased LDL uptake by increasing LDLR (LDL receptor) expression, and promoted cholesterol efflux through increasing expression of LXRα (liver X receptor-α), ABCA1 (ATP-binding cassette subfamily A member 1), ABCG5 (ATP-binding cassette subfamily G member 5), and CYP7A1 (cytochrome P450 family 7 subfamily A member 1). These underlying alterations were confirmed in ASGR1-overexpressing ApoE-/- mice. In addition, ASGR1 deficiency exacerbates liver injury in Western diet-induced Asgr1-/-ApoE-/- mice and high-fat diet-induced but not normal laboratory diet-induced and high-fat and high-cholesterol diet-induced Asgr1-/- mice, while its overexpression mitigates liver injury in Western diet-induced ASGR1-overexpressing ApoE-/- mice. Inhibition of ASGR1 inhibits atherosclerosis in Western diet-fed ApoE-/- mice, suggesting that inhibiting ASGR1 may serve as a novel therapeutic strategy to treat atherosclerosis and cardiovascular diseases.

The effect of acute intragastric vs. intravenous alcohol administration on inflammation markers, blood lipids and gallbladder motility in healthy men.

Ethanol intake increases plasma concentrations of triglycerides and chronic ethanol use impairs lipid metabolism and causes chronic inflammation. The gut plays an important role in metabolic handling of nutrients, including lipids, and a leaky gut associated with alcohol intake, allowing inflammatory signals to the portal vein, has been proposed to constitute a mechanism by which ethanol induces hepatic inflammation. We compared the effects of enteral and parenteral administration of ethanol on a range of circulating inflammation markers (including soluble CD163, a marker of liver macrophage activation), lipids, cholecystokinin (CCK) and fibroblast growth factor 19 (FGF19) as well as gallbladder volume. On two separate and randomized study days, we subjected healthy men (n=12) to double-blinded intragastric ethanol infusion (IGEI) and isoethanolemic intravenous ethanol infusion (IVEI). Blood was sampled and ultrasonographic evaluation of gallbladder volume was performed at frequent intervals for 4h after initiation of ethanol administration on both days. Little or no effects were observed on plasma levels of inflammation markers during IGEI and IVEI, respectively. Circulating levels of total, low-density lipoprotein and high-density lipoprotein cholesterol decreased after ethanol administration independently of the administration form. Triglyceride and very low-density lipoprotein (VLDL) cholesterol concentrations increased more after IGEI compared to IVEI. IVEI had no effect on plasma CCK and caused an increased gallbladder volume whereas IGEI elicited a CCK response (P<0.0001) without affecting gallbladder volume. Circulating FGF19 concentrations decreased equally in response to both ethanol administration forms. In conclusion, by evaluating a range of circulating inflammation markers during IGEI and IVEI we were not able to detect signs of systemic low-grade inflammation originating from the presence of ethanol in the gut. IVEI increased gallbladder volume whereas IGEI increased plasma CCK (with neutral effect on gallbladder volume), increased plasma VLDL cholesterol and triglyceride concentrations; indicating that the enteral route of administration may influence ethanol's effects on lipid metabolism.

Low Very low-Density Lipoprotein Cholesterol but High Very low-Density Lipoprotein Receptor mRNA Expression in Peripheral White Blood Cells: An Atherogenic Phenotype for Atherosclerosis in a Community-Based Population

Very low-density lipoprotein cholesterol (VLDL-C), via binding very low-density lipoprotein receptor (VLDLR), can induce the development of atherosclerosis. Besides monocytes, VLDLR expression is detected in various peripheral white blood cells (WBCs), yet its underlying role remains unclear. We thereby aimed to test the hypothesis that VLDLR in all types of peripheral WBCs may be involved in the association between VLDL-C and atherosclerosis. VLDLR mRNA expression in peripheral WBC and plasma VLDL-C levels were measured in 747 participants from a community-based study. Plaque prevalence and total plaque area (TPA) were used to evaluate the burden of carotid atherosclerosis. VLDL-C was positively associated with atherosclerosis risk, whereas this association was modified by VLDLR mRNA level. In participants with the lowest VLDL-C but the highest VLDLR mRNA expression, the risk for plaque prevalence unexpectedly was the highest. This association was also observed for TPA. Moreover, this association remained unchanged after adjusting for WBC or monocytes. Our findings described an atherogenic phenotype characterized by low VLDL-C but high VLDLR mRNA expression in peripheral WBCs, which suggested that VLDLR in all types of peripheral WBCs may be involved in lipid deposition, and VLDL-C and VLDLR may co-determine the development of atherosclerosis.

Very low density lipoprotein cholesterol associates with coronary artery calcification in type 2 diabetes beyond circulating levels of triglycerides

ObjectiveWhile recent genomic studies have focused attention on triglyceride (TG) rich lipoproteins in cardiovascular disease (CVD), little is known of very low-density lipoprotein cholesterol (VLDL-C) relationship with atherosclerosis and CVD. We examined, in a high-risk type-2 diabetic population, the association of plasma VLDL-C with coronary artery calcification (CAC). MethodsThe Penn Diabetes Heart Study (PDHS) is a cross-sectional study of CVD risk factors in type-2 diabetics (n = 2118, mean age 59.1 years, 36.5% female, 34.1% Black). Plasma lipids including VLDL-C were calculated (n = 1879) after ultracentrifugation. ResultsIn Tobit regression, VLDL-C levels were positively associated with increasing CAC after adjusting for age, race, gender, Framingham risk score, body mass index, C-reactive protein, exercise, medication and alcohol use, hemoglobin A1c, and diabetes duration [Tobit ratio (TR) and 95% confidence interval (CI) 0.38 (0.12–0.65), P = 0.005] and even after inclusion of apolipoprotein B data [TR 0.31 (0.03–0.58), P = 0.030]. Approximately 3-fold stronger effect was observed in women [TR 0.75 (0.16–1.34), P = 0.013] than men [TR 0.20 (−0.10–0.50), P = 0.189; gender interaction P = 0.034]. Plasma VLDL-C was related more strongly to CAC scores than TG levels (e.g., Akaike information criteria of 7263.65 vs. 7263.94) and had stronger CAC association in individuals with TGs >150 mg/dl (TR 0.80, P = 0.010) vs. those with TGs <150 mg/dl (TR 0.27, P = 0.185). ConclusionsIn PDHS, VLDL-C is associated with CAC independent of established CVD risk factors, particularly in women, and may have value even beyond apolipoprotein B levels and in patients with elevated TGs.

Abstracts from the Emerging Science Series, June 19, 2013

Stella Aslibekyan , Marguerite M. Irvin, Jin Sha, Degui Zhi, Univ of Alabama at Birmingham, Birmingham, AL; Krista Stanton Thibeault, Hudson Alpha Inst for Biotechnology, Huntsville, AL; Michael Y. Tsai, Univ of Minnesota, Minneapolis, MN; Paul Hopkins, Univ of Utah, Salt Lake City, UT; Ingrid B. Borecki, Washington Univ at St Louis, St Louis, MO; Jose M. Ordovas, Tufts Univ, Boston, MA; Devin M. Absher, Hudson Alpha Inst for Biotechnology, Huntsville, AL; Donna K. Arnett, Univ of Alabama at Birmingham, Birmingham, AL Introduction: Inter-individual variability in plasma lipid levels and other cardiovascular risk phenotypes is influenced by both genetic and environmental factors. However, known predictors explain only a limited portion of the observed variability. We hypothesized that epigenetic changes such as DNA methylation contribute to the architecture of complex metabolic traits such as plasma lipids and thus affect cardiovascular risk. Methods: We isolated DNA from CD4+ T-cells and quantified methylation at 461,281 CpG sites using the Infinium HumanMethylation450 BeadChip Kit in 888 participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. Participants were randomly allocated to either discovery (n=593) or replication (n=295) data …

Liver specific inactivation of carboxylesterase 3/triacylglycerol hydrolase decreases blood lipids without causing severe steatosis in mice

Carboxylesterase 3/triacylglycerol hydrolase (Ces3/TGH) participates in hepatic very low-density lipoprotein (VLDL) assembly and in adipose tissue basal lipolysis. Global ablation of Ces3/Tgh expression decreases serum triacylglycerol (TG) and nonesterified fatty acid levels and improves insulin sensitivity. To understand the tissue-specific role of Ces3/TGH in lipid and glucose homeostasis, we generated mice with a liver-specific deletion of Ces3/Tgh expression (L-TGH knockout [KO]). Elimination of hepatic Ces3/Tgh expression dramatically decreased plasma VLDL TG and VLDL cholesterol concentrations but only moderately increased liver TG levels in mice fed a standard chow diet. Significantly reduced plasma TG and cholesterol without hepatic steatosis were also observed in L-TGH KO mice challenged with a high-fat, high-cholesterol diet. L-TGH KO mice presented with increased plasma ketone bodies and hepatic fatty acid oxidation. Intrahepatic TG in L-TGH KO mice was stored in significantly smaller lipid droplets. Augmented hepatic TG levels in chow-fed L-TGH KO mice did not affect glucose tolerance or glucose production from hepatocytes, but impaired insulin tolerance was observed in female mice. Our data suggest that ablation of hepatic Ces3/Tgh expression decreases plasma lipid levels without causing severe hepatic steatosis.

Effect of Dietary Coenzyme Q10 on Cholesterol Metabolism in Growing Chickens

Coenzyme Q10 (CoQ10), a potent lipophilic antioxidant, is a naturally occurring compound with a ubiquitous distribution in nature and is used as a dietary supplement to combat aging. In rats, there is evidence that coenzyme Q9, major coenzyme Q homologue in rodents, suppresses hepatic cholesterogenesis and decreases plasma total cholesterol concentration. In this study, we investigated the effect of dietary CoQ10 on cholesterol metabolism in growing chickens. The supplementation of CoQ10 in a diet significantly decreased the total cholesterol levels in the liver and plasma. Plasma very low density lipoprotein (VLDL) cholesterol concentration was significantly decreased by dietary CoQ10. The enzymatic activity of hepatic hydroxymethylglutaryl-coenzyme A reductase (HMGR), the rate-limiting enzyme of the cholesterol synthetic pathway, was significantly decreased by dietary CoQ10, whereas the mRNA level of HMGR was not affected. These findings suggest that dietary CoQ10 suppresses hepatic cholesterogenesis by the inhibition of HMGR activity at the posttranscriptional level in chickens, which in turn decreases plasma VLDL cholesterol concentration.

Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis†

Nonalcoholic steatohepatitis (NASH) involves liver lipid accumulation (steatosis) combined with hepatic inflammation. The transition towards hepatic inflammation represents a key step in pathogenesis, because it will set the stage for further liver damage, culminating in hepatic fibrosis, cirrhosis, and liver cancer. The actual risk factors that drive hepatic inflammation during the progression to NASH remain largely unknown. The role of steatosis and dietary cholesterol in the etiology of diet-induced NASH was investigated using hyperlipidemic mouse models fed a Western diet. Livers of male and female hyperlipidemic (low-density lipoprotein receptor-deficient [ldlr(-/-)] and apolipoprotein E2 knock-in [APOE2ki]) mouse models were compared with livers of normolipidemic wild-type (WT) C57BL/6J mice after short-term feeding with a high-fat diet with cholesterol (HFC) and without cholesterol. Whereas WT mice displayed only steatosis after a short-term HFC diet, female ldlr(-/-) and APOE2ki mice showed steatosis with severe inflammation characterized by infiltration of macrophages and increased nuclear factor kappaB (NF-kappaB) signaling. Remarkably, male ldlr(-/-) and APOE2ki mice developed severe hepatic inflammation in the absence of steatosis after 7 days on an HFC diet compared with WT animals. An HFC diet induced bloated, "foamy" Kupffer cells in male and female ldlr(-/-) and APOE2ki mice. Hepatic inflammation was found to be linked to increased plasma very low-density lipoprotein (VLDL) cholesterol levels. Omitting cholesterol from the HFC diet lowered plasma VLDL cholesterol and prevented the development of inflammation and hepatic foam cells. These findings indicate that dietary cholesterol, possibly in the form of modified plasma lipoproteins, is an important risk factor for the progression to hepatic inflammation in diet-induced NASH.

Increase of Classic and Nonclassic Cardiovascular Risk Factors in Patients with Acromegaly

To evaluate the prevalence of classic and nonclassic cardiovascular risk factors in patients with acromegaly. Sixty-two patients with acromegaly (50 with active disease and 12 with controlled acromegaly) and 36 healthy persons (the control group) underwent measurement of lipids, fasting plasma glucose, homeostasis model assessment of insulin resistance (HOMA-IR) index, Lp(a), high-sensitivity C-reactive protein (hsCRP), homocysteine, and variables primarily related to thrombogenesis (fibrinogen, antithrombin III, protein C, and protein S). In comparison with control subjects, patients with active acromegaly had significantly higher mean values of fasting plasma glucose, total cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein (VLDL) cholesterol, triglycerides, Lp(a), HOMA-IR, and fibrinogen as well as lower mean levels of high-density lipoprotein cholesterol and protein S. In both groups, homocysteine, antithrombin III, protein C, and hsCRP levels were similar. Moreover, patients with active acromegaly, in comparison with those who had controlled acromegaly, presented with significantly higher values of fasting plasma glucose, HOMA-IR, triglycerides, VLDL cholesterol, Lp(a), and fibrinogen, whereas hsCRP and protein S were significantly lower. Finally, low levels of high-density lipoprotein cholesterol and protein S as well as elevated values of VLDL cholesterol, triglycerides, HOMA-IR, and fasting plasma glucose were more prevalent in patients with active acromegaly than in the other groups. Our findings demonstrate that, in comparison with control subjects and patients with controlled acromegaly, patients with active acromegaly had a higher frequency of classic and nonclassic cardiovascular risk factors. These findings are potentially very important because acromegaly is associated with a 2- to 3-fold increase in mortality rate, predominantly related to cardiovascular disease.

Effect of dietary ratios of fatty acids on cholesterol metabolism in rats and on low-density lipoprotein uptake in hepatocytes

The effects of different dietary ratios of polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids (MUFAs) to saturated fatty acids (SFAs) [(PUFA+MUFA)/SFA] on plasma and hepatic lipids, the activities of hepatic regulatory enzymes of cholesterol metabolism, and low-density lipoprotein (LDL) uptake of hepatocytes and Kupffer cells were examined. In this study, 2 different types of diets that had the same PUFA/SFA ratio of 1.0 but each with different (PUFA+MUFA)/SFA ratios of 1.4 (diet 1, control) and 5.7 (diet 2), respectively, were fed to rats. Rats fed with diet 2 showed significantly increased plasma total triacylglycerol (TAG; 21%), very low density lipoprotein (VLDL) TAG (28%), and VLDL cholesterol (113%) levels compared with those fed with diet 1. Plasma LDL cholesterol concentration was not different between the 2 dietary groups of rats. Rats fed with diet 2 also had significantly increased hepatic cholesteryl ester concentrations (155%) and excreted less neutral sterol (35%) compared with rats in the diet 1 group. The activities of hepatic acyl coenzyme A (CoA):cholesterol acyltransferase and cholesterol 7 α-hydroxylase for rats in diet group 2 were significantly increased (38% and 39%, respectively), and hepatic 3-hydroxy-3-methylglutaryl CoA reductase activity decreased (21%) compared with the values in diet group 1. Uptake of LDL by hepatocytes (106%) and Kupffer cells (140%) was higher in rats fed with diet 2 compared with rats fed with diet 1. In summary, the diet with a high ratio (PUFA+MUFA)/SFA increased plasma total TAG, VLDL TAG, and VLDL cholesterol concentrations and liver cholesteryl ester by elevating hepatic acyl CoA:cholesterol acyltransferase and 7 α-hydroxylase activities, lowering hepatic 3-hydroxy-3-methylglutaryl CoA reductase activity, and increasing LDL uptake by hepatocytes and Kupffer cells.

ACAT inhibition reverses LCAT deficiency and improves plasma HDL in chronic renal failure.

Chronic renal failure (CRF) is associated with increased risk of arteriosclerotic cardiovascular disease and profound alteration of plasma lipid profile. Uremic dyslipidemia is marked by increased plasma concentration of ApoB-containing lipoproteins and impaired high-density lipoprotein (HDL)-mediated reverse cholesterol transport. These abnormalities are, in part, due to acquired LCAT deficiency and upregulation of hepatic acyl-CoA:cholesterol acyltransferase (ACAT). ACAT catalyzes intracellular esterification of cholesterol, thereby promoting hepatic production of ApoB-containing lipoproteins and constraining HDL-mediated cholesterol uptake in the peripheral tissues. In view of the above considerations, we tested the hypothesis that pharmacological inhibition of ACAT may ameliorate CRF-induced dyslipidemia. 5/6 Nephrectomized rats were treated with either ACAT inhibitor IC-976 (30 mg.kg(-1).day(-1)) or placebo for 6 wk. Sham-operated rats served as controls. Key cholesterol-regulating enzymes, plasma lipids, and creatinine clearance were measured. The untreated CRF rats exhibited increased plasma low-density lipoprotein (LDL) and very LDL (VLDL) cholesterol, unchanged plasma HDL cholesterol, elevated total cholesterol-to-HDL cholesterol ratio, reduced liver microsomal free cholesterol, and diminished creatinine clearance. This was accompanied by reduced plasma LCAT, increased hepatic ACAT-2 mRNA, ACAT-2 protein and ACAT activity, and unchanged hepatic HMG-CoA reductase and cholesterol 7alpha-hydroxylase. ACAT inhibitor raised plasma HDL cholesterol, lowered LDL and VLDL cholesterol, and normalized total cholesterol-to-HDL cholesterol ratio without changing total cholesterol concentration (hence, a shift from ApoB-containing lipoproteins to HDL). This was accompanied by normalizations of hepatic ACAT activity and plasma LCAT. In conclusion, inhibition of ACAT reversed LCAT deficiency and improved plasma HDL level in CRF rats. Future studies are needed to explore the efficacy of ACAT inhibition in humans with CRF.

Overexpression of Apolipoprotein E3 in Transgenic Rabbits Causes Combined Hyperlipidemia by Stimulating Hepatic VLDL Production and Impairing VLDL Lipolysis

The differential effects of overexpression of human apolipoprotein (apo) E3 on plasma cholesterol and triglyceride metabolism were investigated in transgenic rabbits expressing low (<10 mg/dL), medium (10 to 20 mg/dL), or high (>20 mg/dL) levels of apoE3. Cholesterol levels increased progressively with increasing levels of apoE3, whereas triglyceride levels were not significantly affected at apoE3 levels up to 20 mg/dL but were markedly increased at levels of apoE3 >20 mg/dL. The medium expressers had marked hypercholesterolemia (up to 3- to 4-fold over nontransgenics), characterized by an increase in low density lipoprotein (LDL) cholesterol, while the low expressers had only slightly increased plasma cholesterol levels. The medium expressers displayed an 18-fold increase in LDL but also had a 2-fold increase in hepatic very low density lipoprotein (VLDL) triglyceride production, an 8-fold increase in VLDL apoB, and a moderate decrease in the ability of the VLDL to be lipolyzed. However, plasma clearance of VLDL was increased, likely because of the increased apoE3 content. The increase in LDL appears to be due to an enhanced competition of VLDL for LDL receptor binding and uptake, resulting in the accumulation of LDL. The combined hyperlipidemia of the apoE3 high expressers (>20 mg/dL) was characterized by a 19-fold increase in LDL cholesterol but also a 4-fold increase in hepatic VLDL triglyceride production associated with a marked elevation of plasma VLDL triglycerides, cholesterol, and apoB100 (4-, 9-, and 25-fold over nontransgenics, respectively). The VLDL from the high expressers was much more enriched in apoE3 and markedly depleted in apoC-II, which contributed to a >60% inhibition of VLDL lipolysis. The combined effects of stimulated VLDL production and impaired VLDL lipolysis accounted for the increases in plasma triglyceride and VLDL concentrations in the apoE3 high expressers. The hyperlipidemic apoE3 rabbits have phenotypes similar to those of familial combined hyperlipidemia, in which VLDL overproduction is a major biochemical feature. Overall, elevated expression of apoE3 appears to determine plasma lipid levels by stimulating hepatic VLDL production, enhancing VLDL clearance, and inhibiting VLDL lipolysis. Thus, the differential expression of apoE may, within a rather narrow range of concentrations, play a critical role in modulating plasma cholesterol and triglyceride levels and may represent an important determinant of specific types of hyperlipoproteinemia.

The effect of plasma low density lipoprotein apheresis on the hepatic secretion of biliary lipids in humans

Background—The liver is a key organ in the metabolism of cholesterol in humans. It is the only organ by which substantial amounts of cholesterol are excreted from the body, either...

Effect of Pravastatin in the Treatment of Patients with Type III Hyperlipoproteinemia.

OBJECTIVE: To determine the efficacy and safety of pravastatin in the treatment of subjects with Type III hyperlipoproteinemia. DESIGN: Randomized, double-blind, placebo-controlled, crossover study. SETTING: Four lipid research clinics in the United States. PATIENTS: Twenty subjects between 18 and 70 years old with three diagnostic features of Type III hyperlipoproteinemia: very-low-density lipoprotein cholesterol (VLDL-C)/total plasma triglyceride ratio in excess of 0.30; beta-migrating VLDL pattern on agarose-gel electrophoresis; and the homozygous apolipoprotein E phenotype E(2)/E(2). After 4 weeks of dietary control, the subjects were eligible if their mean plasma total cholesterol level was at least 250 mg/dl and mean plasma trigylceraide level was at least 220 mg/dL. INTERVENTIONS: Subjects were randomly assigned to pravastatin 40 mg hs or placebo hs at the start of the first 6-week double-blind treatment period. After completing this phase, subjects entered a 4-week placebo/drug washout phase before crossing over to the opposite treatment for the second 6-week double-blind treatment period. MEASUREMENTS: Plasma VLDL-C and low density lipoprotein cholesterol (LDL-C) after ultracentrifugation and total triglyceride, cholesterol and high-density lipoprotein cholesterol (HDL-C) after 6 weeks of treatment; adverse clinical events and abnormal laboratory results. RESULTS: After 6 weeks of pravastatin theraphy, plasma levels of VLDL-C and LDL-C decreased 49% and 39%, respectively (p less-than-or-equal 0.01 vs. placebo). Total cholesterol and triglyceride concentrations decreased 36% and 22%, respectively (p less-than-or-equal 0.001 vs. placebo). Levels of HDL-C increased 8% (p less-than-or-equal 0.01 vs. placebo). Pravastatin was tolerated well. One marked laboratory abnormality, an asymptomatic elevation of creatine phosphokinase, resolved upon completing pravastatin treatment. CONCLUSIONS: Pravastatin lowers plasma VLDL-C, LDL-C, total cholesterol, and triglyceride and raises HDL-C in subjects with Type III hyperlipoproteinemia. The safety profile is excellent. Pravastatin reductase inhibitor therapy affords a useful approach to the management of Type III or remnant removal disease.

Simvastatin improves chylomicron remnant removal in familial combined hyperlipidemia without changing chylomicron conversion

It is unknown whether the clearance of atherogenic chylomicron remnants and the postprandial lipoprotein metabolism in general can be improved by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in subjects with familial combined hyperlipidemia (FCH). Therefore, the postprandial chylomicron remnant clearance was studied in nine normolipidemic untreated controls and seven FCH patients before and after treatment with simvastatin using an oral vitamin A-fat load (24 hours, 50 g/m 2). Treatment with simvastatin reduced plasma cholesterol level by 16% (mean ± SEM, 8.1 ± 0.8 v 6.8 ± 0.8 mmol/L; P < .05) and plasma apolipoprotein (apo) B level by 19% (1.6 ± 0.2 v 1.3 ± 0.2 g/L; P < .05). Plasma apo E level (89.6 ± 21.0 mg/L) was reduced by 29% (63.5 ± 14.1 mg/L; P < .05). High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels did not change; consequently, the reductions seen had been due to a decrease in very-low-density lipoprotein (VLDL) levels. Fasting plasma triglyceride (30% reduction) and plasma apo C-II (31% reduction) levels did not change significantly. Mean postheparin plasma lipoprotein lipase (LPL) activity increased by 13% after treatment (90.4 ± 19.8 v 102.6 ± 20.3 mU/mL; P < .05), but hepatic lipase (HL) activity was not altered. The clearance of chylomicrons (Sf > 1,000), expressed as the area under the 24-hour retinyl palmitate curve, did not change with simvastatin (52.8 ± 12.9 v 51.8 ± 13.4 h · mg −1/L). In contrast, chylomicron remnant (Sf < 1,000) clearance (62.9 ± 11.1 h · mg −1/L) improved after treatment (53.3 ± 11.3 h · mg −1/L; P = .02). In conclusion, the reduction in plasma apo E concentration and the improvement in retinyl palmitate kinetics indicated enhanced chylomicron remnant removal in FCH subjects by simvastatin. An increased activity of LPL was the most likely factor contributing to the increased chylomicron remnant clearance. The atherosclerosis risk profile in FCH improved during simvastatin treatment as evidenced by decreased plasma VLDL cholesterol and apo B levels and increased chylomicron remnant removal.

Dietary fish oil decreases VLDL production rates

The purpose of the study was to evaluate whether the hypocholesterolemic effect of fish oil in roosters (10% fish oil vs. 10% corn oil in the diet) is due to a decrease in very-low-density lipoprotein (VLDL) secretion rate. Previous studies have shown that in vivo inhibition of lipoprotein lipase with a specific antiserum quantitatively blocks VLDL catabolism. Secretion of VLDL cholesterol and triacylglycerol in fasting roosters was measured during a 4 h inhibition of lipoprotein lipase. Secretion rates of VLDL cholesterol and triacylglycerol were 39% lower ( P < 0.03) and 49% lower ( P < 0.025), respectively, with the fish oil diet. VLDL composition at the end of the inhibition was not remarkably different between treatments. Smaller portomicrons were produced by fish oil feeding ( 1737 ± 120 vs. 2090 ± 64 A ̊ , P < 0.01 ), but there were no differences seen in K m or V max when portomicrons were incubated with purified avian lipoprotein lipase. Plasma cholesterol and triacylglycerol levels were not affected by the oil supplements. In a second study, the diets were supplemented with 0.5% cholesterol in addition to the oils. Fasting serum cholesterol was 52% lower ( P < 0.05) in the fish oil-fed birds, most of the difference being in the VLDL fraction (11.5 ± 9 vs. 99.7 ± 66 mg/ dl). Low-density lipoprotein cholesterol was also significantly lower. VLDL cholesterol and triacylglycerol secretion rates were lower by 39 ( P < 0.025) and 38% ( P < 0.06), respectively, in the fish oil group. VLDL from fish oil-fed birds collected after a 4 h inhibition had a lower cholesterol content than that from the corn oil-fed birds (15.9 ± 2.8 vs. 21.2 ± 1.9 wt%, P < 0.025). In the fish oil-fed animals the decrease in VLDL cholesterol secretion accounted for 61% of the observed decrease in VLDL cholesterol. The balance of the decrease in plasma VLDL cholesterol was due to a significant increase in VLDL cholesterol fractional removal rate in the fish oil-fed animals from 0.45 ± 1.0 to 2.63 ± 1.7 h −1 ( P < 0.01).

Plasma Very Low Density Lipoprotein (VLDL) in Cholesterol-Fed Rabbits: Chylomicron Remnants or Liver Lipoproteins?

When iodinated hypercholesterolemic plasma very low density lipoprotein (VLDL), chylomicrons or chylomicron remnants were injected intravenously, the apoB of chylomicrons and chylomicron remnants was removed more rapidly than apoB of hypercholesterolemic VLDL. In perfused livers from normal or cholesterol-fed rabbits, chylomicron remnants were removed 69% and 125% more rapidly, respectively, than hypercholesterolemic VLDL. Chylomicron remnants were removed equally well by perfused livers from normal and cholesterol-fed rabbits, but hypercho-lesterolemic plasma VLDL was removed more slowly by perfused livers of cholesterol-fed than by those of normal rabbits. Chylomicron remnant removal by livers from normal and cholesterol-fed rabbits was inhibited by high levels of hypercholesterolemic plasma VLDL in the perfusate. Twenty-four hours after a single dose of retinyl ester was fed to cholesterol-fed rabbits, less than 1% of the absorbed retinol remained in the plasma as retinyl ester. Thus, increases in plasma VLDL cholesterol levels in cholesterol-fed rabbits cannot be accounted for by the accumulation of chylomicron remnants. Apparently, a cholesterol-rich VLDL, probably of hepatic origin, accumulates in the postabsorptive plasma of the cholesterol-fed rabbit.

The Effect of Dietary Manganese Deficiency on Cholesterol and Lipid Metabolism in the Wistar Rat and in the Genetically Hypercholesterolemic RICO Rat

Two experiments were conducted to determine the effect of dietary manganese on cholesterol and lipid metabolism in the Wistar rat and the genetically hypercholesterolemic RICO rat. Weanling animals were placed on a manganese-deficient (0.12 µg/g) and a supplemented diet (100.12 µg/g). Mean body weights, hepatic fatty acid synthesis and liver manganese concentration significantly decreased in the deficient group of Wistar rats. Plasma cholesterol, VLDL (very low density lipoprotein) and HDL (high-density lipoprotein) cholesterol, hepatic cholesterol synthesis, liver cholesterol and lipid concentrations were not significantly affected by manganese deficiency. Mean body weights and hepatic manganese content were lower in the manganese-deficient group in both normal and hypercholesterolemic RICO rats. Manganese deficiency significantly decreased LDL cholesterol concentration in the hypercholesterolemic RICO rats. Manganese deficiency had no significant effect on hepatic cholesterol and fatty acid synthesis, plasma cholesterol, VLDL and HDL cholesterol concentrations, liver lipid and liver cholesterol concentration in either group of RICO rats. These results indicate that dietary manganese deficiency does not result in significant alterations in cholesterol and lipid metabolism in the rat.

Effect of phenobarbitone on plasma lipids in normal subjects.

1. Phenobarbitone in a dose of 180 mg daily was administered to ten normal subjects for 3 weeks. There was a significant increase in total plasma cholesterol, plasma low-density-lipoprotein cholesterol, plasma low-density-lipoprotein (LDL) triglycerides and plasma LDL protein. The increase in plasma LDL cholesterol accounted for the increase in total plasma cholesterol. There was a significant reduction in the ratio of LDL cholesterol to LDL protein. 2. No significant changes were observed in total plasma triglycerides, plasma very-low-density-lipoprotein (VLDL) triglycerides, plasma VLDL cholesterol or plasma VLDL protein. 3. Evidence that drug-metabolizing enzymes were induced by phenobarbitone was provided by an increase in antipyrine clearance. No relationship was observed between changes in plasma cholesterol and changes in antipyrine clearance. Serum gamma-glutamyl transpeptidase was also increased after phenobarbitone administration, the increase being unrelated to changes in antipyrine clearance or plasma cholesterol.