Effects of a frequent apolipoprotein E isoform, ApoE4Freiburg (Leu28-->Pro), on lipoproteins and the prevalence of coronary artery disease in whites. (1/189)

Different isoforms of apoE modulate the concentrations of plasma lipoproteins and the risk for atherosclerosis. A novel apoE isoform, apoE4Freiburg, was detected in plasma by isoelectric focusing because its isoelectric point is slightly more acidic than that of apoE4. ApoE4Freiburg results from a base exchange in the APOE4 gene that causes the replacement of a leucine by a proline at position 28. Analysis of the allelic frequencies in whites in southwestern Germany revealed that this isoform is frequent among control subjects (10:4264 alleles) and is even more frequent in patients with coronary artery disease (21:2874 alleles; P=0.004; adjusted odds ratio, 3.09; 95% confidence interval, 1.20 to 7.97). ApoE4Freiburg affects serum lipoproteins by lowering cholesterol, apoB, and apoA-I compared with apoE4 (P<0.05). Our 4 apoE4Freiburg homozygotes suffered from various phenotypes of hyperlipoproteinemia (types IIa, IIb, IV, and V). In vitro binding studies excluded a binding defect of apoE4Freiburg, and in vivo studies excluded an abnormal accumulation of chylomicron remnants. ApoE4Freiburg and apoE4 accumulated to a similar extent in triglyceride-rich lipoproteins. HDLs, however, contained about 40% less apoE4Freiburg than apoE4. In conclusion, our data indicate that apoE4Freiburg exerts its possible atherogenic properties by affecting the metabolism of triglyceride-rich lipoproteins and HDL.  (+info)

Genetic deficiency of acylation stimulating protein (ASP(C3ades-Arg)) does not cause hyperapobetalipoproteinemia in mice. (2/189)

The acylation stimulating protein (ASP) is a 76-amino acid peptide that has been proposed as a potent mediator of triglyceride synthesis and, when functionally impaired, as a major cause of hyperapobetalipoproteinemia (HyperapoB). Purification and sequence analysis of ASP from human sera have revealed that ASP is identical to the complement C3-derived activation peptide C3ades-Arg. Because C3 is the precursor for C3ades-Arg and therefore ASP, a deficiency in C3 would be predicted to result in a phenotype characteristic of HyperapoB. To test this hypothesis in vivo, the current study was undertaken in which ASP(C3ades-Arg)-deficient mice were used as a model system. No significant differences were found in the triglyceride, cholesterol, or free fatty acid concentrations in the plasma of fasted normal and ASP(C3ades-Arg)-deficient animals. In addition, plasma lipoprotein analyses indicated that the very low density lipoprotein, low density lipoprotein, and high density lipoprotein cholesterol and triglyceride concentrations as well as the apolipoprotein B-48 and B-100 levels were not significantly different in the plasma of ASP(C3ades-Arg)-deficient and wild type mice. Furthermore, when challenged with an oral fat load, the ASP(C3ades-Arg)-deficient mice showed no impaired ability to clear triglycerides and free fatty acids from their circulation when compared with their wild-type littermates. Collectively, these results indicate that ASP(C3ades-Arg) deficiency does not cause HyperapoB in mice and that the physiological importance of impaired ASP(C3ades-Arg) function as a cause of hyperapobetalipoproteinemia needs to be reevaluated.  (+info)

Infusion of lipoproteins into volunteers enhances the growth of Candida albicans. (3/189)

Infusion of reconstituted high-density lipoproteins (rHDL) is being studied in clinical trials as an adjunctive therapy for gram-negative sepsis. Since no data are available on its possible effects in systemic candidiasis, we investigated the effect of rHDL infusion into volunteers on the growth of Candida albicans. C. albicans growth was 10- to 100-fold higher in the plasma of volunteers infused with 80 or 100 mg/kg rHDL than in plasma collected before infusion; administration of 60 mg/kg rHDL had marginal effects. In vitro, the isolated lipoprotein subfractions had a growth-promoting effect on C. albicans. These data suggest potential adverse effects of rHDL if infused into patients with systemic candidiasis. Thus, rHDL infusion into patients with sepsis caused by an unknown microorganism may be contraindicated.  (+info)

Beneficial effects of ACTH on the serum lipoprotein profile and glomerular function in patients with membranous nephropathy. (4/189)

BACKGROUND: Previous studies have shown that short-term treatment with adrenocorticotrophic hormone (ACTH) has a strong and rapid lipid-lowering effect. In this long-term study of nephrotic patients with idiopathic membranous nephropathy, the influence of ACTH on the serum lipoprotein profile and glomerular function as well as the dose-effect relationship was investigated. METHODS: Fourteen patients received ACTH intramuscularly at increasing doses during 56 days. Serum concentrations of lipids, lipoproteins, and apolipoproteins as well as variables of glomerular function were analyzed, and the side-effects were recorded. ACTH treatment, in the estimated optimal dosage, was then continued in five patients with severe steroid-resistant nephrotic syndrome. In these five patients, the total treatment period was 12 months, and the follow-up time after discontinuing treatment was 18 months. RESULTS: Taking both the statistically significant therapeutic effects and the modest side-effects into consideration, the optimal dosage of ACTH was estimated to be 1 mg twice per week. At that dose, reductions by 30 to 60% in the serum concentrations of cholesterol, triglycerides, apolipoprotein B, and lipoprotein(a) were observed, whereas the serum concentrations of high-density lipoprotein cholesterol and apolipoprotein AI rose by 30 to 40%. In addition, the urinary albumin excretion decreased by 90%, and the glomerular filtration rate increased by 25%. Deterioration was observed in all cases when ACTH was discontinued after a treatment duration of 56 days. However, the five patients in whom ACTH therapy was resumed were still in remission 18 months after discontinuance of treatment. CONCLUSIONS: In nephrotic patients with idiopathic membranous nephropathy, treatment with ACTH 1 mg twice per week was associated with significant long-term improvements in serum lipoprotein pattern and glomerular function.  (+info)

Cyclosporin-induced dyslipoproteinemia is associated with selective activation of SREBP-2. (5/189)

The use of cyclosporin A has contributed greatly to the success of organ transplantation. However, cyclosporin-associated side effects of hypertension, nephrotoxicity, and dyslipoproteinemia have tempered these benefits. Cyclosporin-induced dyslipoproteinemia may be an important risk factor for the accelerated atherosclerosis observed posttransplantation. Using a mouse model, we treated Swiss-Webster mice for 6 days with a daily dose of 20 microg/g body wt of cyclosporin and observed significant elevations of plasma cholesterol, triglyceride, and apolipoprotein B (apoB) levels relative to vehicle-alone treated control animals. Measurement of the rate of secretion of very low-density lipoprotein (VLDL) by the liver in vivo showed that cyclosporin treatment led to a significant increase in the rate of hepatic VLDL triglyceride secretion. Total apoB secretion was unaffected. Northern analysis showed that cyclosporin A treatment increased the abundance of hepatic mRNA levels for a number of key genes involved in cholesterol biosynthesis relative to vehicle-alone treated animals. Two key transcriptional factors, sterol regulatory element-binding protein (SREBP)-1 and SREBP-2, also showed differential expression; SREBP-2 expression was increased at the mRNA level, and there was an increase in the active nuclear form, whereas the mRNA and the nuclear form of SREBP-1 were reduced. These results show that the molecular mechanisms by which cyclosporin causes dyslipoproteinemia may, in part, be mediated by selective activation of SREBP-2, leading to enhanced expression of lipid metabolism genes and hepatic secretion of VLDL triglyceride.  (+info)

Compound heterozygosity for a Wolman mutation is frequent among patients with cholesteryl ester storage disease. (6/189)

Cholesteryl ester storage disease and Wolman disease are rare autosomal recessive lipoprotein-processing disorders caused by mutations in the gene encoding human lysosomal acid lipase. Thus far we have elucidated the genetic defects in 15 unrelated CESD patients. Seven were homozygotes for the prevalent hLAL exon 8 splice junction mutation which results in incomplete exon skipping, while eight probands were compound heterozygotes for E8SJM and a rare mutation on the second chromosome. In this report, we describe the molecular basis of CESD in three compound heterozygous subjects of Czech and Irish origin. RFLP and DNA sequence analysis revealed that they were heteroallelic for the common G(934)-->A substitution in exon 8 of the hLAL gene and a mutation which, if inherited on both alleles, would be expected to result in complete loss of enzyme activity and to cause Wolman disease. In patients A. M. and J. J., two nucleotide deletions in exons 7 and 10 were detected, involving a T at position 722, 723, or 724 and a G in a stretch of five guanosines at positions 1064;-1068 of the hLAL cDNA. Both mutations result in premature termination of protein translation at residues 219 and 336, respectively, and in the production of truncated, inactive enzymes. Subject D. H., in contrast, is a compound heterozygote for the Arg(44)-->Stop mutation previously described in a French CESD proband. Combined with data in the literature, our results demonstrate that compound heterozygosity for a mutation causing Wolman disease is common among cholesteryl ester storage disease patients.  (+info)

Carbohydrate-induced hypertriacylglycerolemia: historical perspective and review of biological mechanisms. (7/189)

Current trends in health promotion emphasize the importance of reducing dietary fat intake. However, as dietary fat is reduced, the dietary carbohydrate content typically rises and the desired reduction in plasma cholesterol concentrations is frequently accompanied by an elevation of plasma triacylglycerol. We review the phenomenon of carbohydrate-induced hypertriacylglycerolemia, the health effects of which are among the most controversial and important issues in public health nutrition today. We first focus on how seminal observations made in the late 1950s and early 1960s became the basis for subsequent important research questions and areas of scientific study. The second focus of this paper is on the current knowledge of biological mechanisms that contribute to carbohydrate-induced hypertriacylglycerolemia. The clinical rationale behind mechanistic studies is this: if carbohydrate-induced hypertriacylglycerolemia shares a metabolic basis with endogenous hypertriacylglycerolemia (that observed in subjects consuming high-fat diets), then a similar atherogenic risk may be more likely than if the underlying metabolic mechanisms differ. The third focus of the paper is on both the positive metabolic changes that occur when high-carbohydrate diets are consumed and the potentially negative health effects of such diets. The review concludes with a summary of some important research questions that remain to be addressed. These issues include the level of dietary carbohydrate that induces carbohydrate-induced hypertriacylglycerolemia, whether the phenomenon is transient or can be avoided, whether de novo lipogenesis contributes to the phenomenon, and what magnitude of triacylglycerol elevation represents an increase in disease risk.  (+info)

The Arg123-Tyr166 central domain of human ApoAI is critical for lecithin:cholesterol acyltransferase-induced hyperalphalipoproteinemia and HDL remodeling in transgenic mice. (8/189)

High density lipoprotein (HDL) metabolism and lecithin:cholesterol acyltransferase (LCAT)-induced HDL remodeling were investigated in transgenic mice expressing human apolipoprotein (apo) AI or an apoAI/apoAII chimera in which the Arg123-Tyr166 domain of apoAI was substituted with the Ser12-Ala75 domain of apoAII. Expression of apoAI and of the apoAI/apoAII chimera resulted in a respective 3. 5-fold and 2.9-fold increase of HDL cholesterol. Human LCAT gene transfer into apoAI-transgenic mice resulted in a 5.1-fold increase of endogenous LCAT activity. This increase was associated with a 2. 4-fold increase of the cholesterol ester-to-free cholesterol ratio of HDL, a shift from HDL(3) to HDL(2), and a 2.4-fold increase of HDL cholesterol levels. Agarose gel electrophoresis revealed that human LCAT gene transfer into human apoAI-transgenic mice resulted in an increase of pre-beta-HDL and of pre-alpha-HDL. In contrast, human LCAT gene transfer did not affect cholesterol levels and HDL distribution profile in mice expressing the apoAI/apoAII chimera. Mouse LCAT did not "see" a difference between wild-type and mutant human apoAI, whereas human LCAT did, thus localizing the species-specific interaction in the central domain of apoAI. In conclusion, the Arg123-Tyr166 central domain of apoAI is not critical for in vivo lipoprotein association. It is, however, critical for LCAT-induced hyperalphalipoproteinemia and HDL remodeling independent of the lipid-binding properties of apoAI.  (+info)

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