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Biomedical subjects

J L Breslow

Publications and source records attributed to J L Breslow.

At least 19 recordsLinked to original sources
PubMed1992

Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells.

apoE-deficient mice have been created by homologous recombination in ES cells. On a low fat, low cholesterol chow diet these animals have plasma cholesterol levels of 494 mg/dl compared with 60 mg/dl in control animals, and when challenged with a high fat Western-type diet, these animals have plasma cholesterol levels of 1821 mg/dl compared with 132 mg/dl in controls. This marked hypercholesterolemia is primarily due to elevated levels of very low and intermediate density lipoproteins. At 10 weeks of age, apoE-deficient mice have already developed atherosclerotic lesions in the aorta and coronary and pulmonary arteries. apoE-deficient mice are a promising small animal model to help understand the role of apoE in vivo and the genetic and environmental determinants of atherosclerosis.

Animals↗
PubMed1992

Apolipoprotein genes and atherosclerosis.

In order to elucidate the genetic abnormalities underlying lipoprotein disorders associated with coronary heart disease susceptibility, researchers have looked for candidate genes. The studies have focused particularly on the lipoprotein transport genes. Relatively common as well as rare mutations have already been identified in several of these genes. In addition, further metabolic and genetic studies indicate that some of these loci harbor significant, but as yet undefined, genetic variation. In the next few years, it is not unreasonable to expect that all or most of the significant mutations at these loci will be catalogued. It is too early to know whether this will be sufficient to explain the genetic basis of altered lipoprotein levels or whether new loci will need to be investigated. Additional candidate gene loci might be those coding for genes involved in intracellular cholesterol metabolism, cholesterol absorption, or insulin resistance. New loci may also be revealed by the technique of reverse genetics. A more complete understanding of the genetics of atherosclerosis susceptibility will probably also entail the identification of variants at genetic loci that control both the reaction of the blood vessel wall to atherogenic lipoproteins and the thrombosis system. Investigation of the genetic basis of coronary heart disease susceptibility remains a worthwhile and lively field, with important clinical and public health ramifications.

Cholesterol↗
PubMed1992

Characterization of the mouse apolipoprotein Apoa-1/Apoc-3 gene locus: genomic, mRNA, and protein sequences with comparisons to other species.

In this report we present the genomic, cDNA, and predicted protein sequences for mouse apolipoproteins A-I and CIII, as well as sequence comparisons with other species. The genes for these apolipoproteins are within 2.5 kb of each other and convergently transcribed. The almost 9 kb of genomic sequence presented extends from 1298 bp 5' to the apolipoprotein A-I (Apoa-1) gene to 1249 bp 5' to the apolipoprotein CIII (Apoc-3) gene. The mouse Apoa-1 gene is 1.76 kb in length with four exons and three introns. The 5' flanking region contains TATA and CCAAT box sequences, an interferon responsive element homology, and potential binding sites for transcription factors CTF/NF1 and HNF4. Translation of the cDNA predicts that the mouse Apoa-1 primary transcript is 264 amino acids. The mouse Apoc-3 gene is 2.2 kb in length and also consists of four exons and three introns. The 5' flanking region contains TATA and CCAAT box sequences, RXR-1 and ARP-1 binding sites, and potential binding sites for transcription factors HNF4, NFkB, AP-1, and CTF/NF1. Translation of the cDNA predicts that the mouse Apoc-3 primary transcript is 99 amino acids. The clustering and genomic organization of the mouse Apoa-1 and Apoc-3 genes are similar to those of the rat and human genes. Significant sequence homologies between species exist for the proximal promoter and exonic regions of each gene, but not for the intronic or intergenic regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

The genetic basis of lipoprotein disorders. Introduction and overview.

In order to elucidate the genetic abnormalities underlying lipoprotein disorders associated with susceptibility to coronary heart disease, researchers have looked for candidate genes. The studies have focused particularly on the lipoprotein transport genes. Relatively common as well as rare mutations have already been identified in several of these genes. In addition, further metabolic and genetic studies indicate that some of these loci harbour significant, but as yet undefined, genetic variation. In the next few years, it is not unreasonable to expect that all or most of the significant mutations at these loci will be catalogued. It is too early to know whether this will be sufficient to explain the genetic basis of altered lipoprotein levels, or whether new loci will need to be investigated. Additional candidate gene loci might be those coding for genes involved in intracellular cholesterol metabolism, cholesterol absorption or insulin resistance. New loci may also be revealed by the technique of reverse genetics. A more complete understanding of the genetics of susceptibility to atheroscerosis will probably also entail the identification of variants at genetic loci that control both the reaction of the blood vessel wall to atherogenic lipoproteins and the thrombosis system. Investigation of the genetic basis of susceptibility to coronary heart disease remains a worthwhile and lively field, with important implications for clinical and public health.

Cholesterol↗
PubMed1992

Decreased HDL2 and HDL3 cholesterol, Apo A-I and Apo A-II, and increased risk of myocardial infarction.

BACKGROUND: A large and consistent body of evidence supports the judgment that elevation of total plasma blood cholesterol is a cause of myocardial infarction (MI) and that high levels of low density lipoprotein (LDL) cholesterol have a positive relation and high levels of high density lipoprotein (HDL) cholesterol an inverse relation with MI. At present, however, the roles, if any, of the major subfractions of HDL, namely, HDL2 and HDL3, have not been clarified. In addition, the relation of plasma apolipoprotein concentrations to MI and whether they provide predictive information over and above their lipoprotein cholesterol associations is unknown. METHODS AND RESULTS: We evaluated these questions in a case-control study of patients hospitalized with a first MI and neighborhood controls of the same age and sex. Cases had significantly lower levels of total HDL (p less than 0.0001) as well as HDL2 (p less than 0.0001) and HDL3 (p less than 0.0001) cholesterol. These differences persisted after controlling for a large number of demographic, medical history, and behavioral risk factors and levels of other lipids. There were significant (p less than 0.0001) inverse dose-response relations with odds ratios for those in the highest quartile relative to those in the lowest of 0.15 for total HDL, 0.17 for HDL2, and 0.29 for HDL3 cholesterol levels. Levels of LDL and very low density lipoprotein cholesterol and triglycerides were also higher among cases than controls, but only for triglycerides was the difference statistically significant after adjustment for coronary risk factors and other lipids (p = 0.044). Apolipoproteins A-I and A-II were both significantly (p less than 0.0001) lower in cases, and differences remained even after adjustment for coronary risk factors and lipids. There were significant dose-response relations for both apolipoprotein A-I (p = 0.026) and A-II (p = 0.002). Neither apolipoprotein B nor E was significantly related to MI after adjustment for lipids and other coronary risk factors. When all four apolipoproteins were taken together, there was an increased level of prediction of MI over the information provided by the lipids and other coronary risk factors (p = 0.003), but this appeared present only for the individual apolipoproteins A-I (p = 0.027) and A-II (p = 0.011). CONCLUSIONS: These data indicate that both HDL2 and HDL3 cholesterol levels are significantly associated with MI. They also raise the possibility that apolipoprotein levels, especially A-I and A-II, may add importantly relevant information to determination of risk of MI.

Age Factors↗
PubMed1992

Polymorphism in the human apolipoprotein A-I gene promoter region. Association of the minor allele with decreased production rate in vivo and promoter activity in vitro.

We investigated a common polymorphism in the human apolipoprotein A-I gene promoter at a position 76 bp upstream of the transcriptional start site. 54 human subjects, whose apoAI production rates had been determined by apoAI turnover studies, were genotyped at this polymorphic position by a novel technique using polymerase chain reaction followed by primer extension. 35 subjects were homozygous for a guanosine (G) at this locus and 19 were heterozygous with a guanosine and adenosine (A). The apoAI production rates were significantly lower (by 11%) in the G/A heterozygotes than in the G homozygotes (P = 0.025). In spite of the apparent effect of this apoAI gene promoter polymorphism on the apoAI production rate, there was no effect on HDL cholesterol or apoAI levels. To investigate whether the observed difference in apoAI production rates was related to differential gene expression of the two alleles, promoters containing either allele were linked to the reporter gene chloramphenicol acetyltransferase, and relative promoter efficiencies were determined after transfection into the human HepG2 hepatoma cell line. The A allele expressed only 68% +/- 5% as well as the G allele, a result consistent with the in vivo apoAI production rate data.

Alleles↗
PubMed1992

An interaction between the human cholesteryl ester transfer protein (CETP) and apolipoprotein A-I genes in transgenic mice results in a profound CETP-mediated depression of high density lipoprotein cholesterol levels.

We have previously described two transgenic mouse lines, one heterozygous for the human apo A-I gene and the other heterozygous for a human cholesteryl ester transfer protein (CETP) minigene driven by the mouse metallothionein-I gene promoter. In the current study, these two lines were crossed producing control, HuCETPTg, HuAITg, and HuAICETPTg mice to study the influence of CETP on HDL cholesterol levels, particle size distribution, and metabolism in animals with mouse and human-like HDL. In the HuCETPTg and HuAICETPTg animals, zinc induction approximately doubled plasma CETP activity, with no activity in plasma from the control and HuAITg animals. The only significant effect of CETP on lipoprotein subfraction cholesterol concentrations was for HDL-C. Compared to control animals, HuCETPTg animals had lower HDL-C, 20% before and 35% after Zn induction, and compared to HuAITg animals, HuAICETPTg animals had lower HDL-C, 35% before and 66% after Zn induction. Control and HuCETPTg HDL consist primarily of a single size population with a mean diameter of 10.00 +/- 0.10 nm and 9.71 +/- 0.05 nm, respectively. HuAITg HDL consists primarily of three distinct HDL size subpopulations with peak diameters of 10.35 +/- 0.08 nm, 8.80 +/- 0.06 nm, 7.40 +/- 0.10 nm, and HuAICETPTg HDL also consists primarily of three distinct HDL size subpopulations with peak diameters of 9.87 +/- 0.05 nm, 8.60 +/- 0.10 nm, 7.30 +/- 0.15 nm before, and 9.71 +/- 0.08 nm, 8.50 +/- 0.11 nm, 7.27 +/- 0.15 nm after zinc induction, respectively. Western blotting analysis of nondenaturing gradient gels of plasma with a monoclonal antibody to CETP indicated that in HuCETPTg and HuAICETPTg mice, 22 and 100%, respectively, of the CETP was HDL associated. Turnover studies with HDL doubly labeled with 125I apo A-I and 3H cholesteryl linoleate indicated that the CETP-induced fall in HDL-C was associated with increased HDL-cholesterol ester fractional catabolic rate in both the absence and presence of human apo A-I, suggesting CETP-mediated transfer of HDL-cholesterol ester to apo B-containing lipoproteins. In summary, these studies suggest that CETP has a much more profound effect on HDL cholesterol levels in transgenic animals expressing human apo A-I. This may be due to an enhanced interaction of CETP with human compared to mouse apo A-I or to the HDL particles they produce.

Animals↗
PubMed1992

Dietary cholesterol increases transcription of the human cholesteryl ester transfer protein gene in transgenic mice. Dependence on natural flanking sequences.

To investigate the regulation of expression of the human cholesteryl ester transfer protein (CETP) gene, transgenic mice were prepared using a CETP minigene linked to the natural flanking sequences of the human CETP gene. By using a transgene containing 3.2 kb of upstream and 2.0 kb of downstream flanking sequence, five different lines of transgenic mice were generated. The abundance of CETP mRNA in various tissues was determined on standard laboratory diet or high fat, high cholesterol diets. In three lines of transgenic mice the tissues expressing the human CETP mRNA were similar to those in humans (liver, spleen, small intestine, kidney, and adipose tissue); in two lines expression was more restricted. There was a marked (4-10-fold) induction of liver CETP mRNA in response to a high fat, high cholesterol diet. The increase in hepatic CETP mRNA was accompanied by a fivefold increase in transcription rate of the CETP transgene, and a 2.5-fold increase in plasma CETP mass and activity. In contrast, CETP transgenic mice, in which the CETP minigene was linked to a metallothionein promoter rather than to its own flanking sequences, showed no change in liver CETP mRNA in response to a high cholesterol diet. Thus (a) the CETP minigene or natural flanking sequences contain elements directing authentic tissue-specific expression; (b) a high cholesterol diet induces CETP transgene transcription, causing increased hepatic CETP mRNA and plasma CETP; (c) this cholesterol response requires DNA sequences contained in the natural flanking regions of the human CETP gene.

Animals↗
PubMed1992

Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles.

Hypertriglyceridemia is common in the general population, but its mechanism is largely unknown. In previous work human apo CIII transgenic (HuCIIITg) mice were found to have elevated triglyceride levels. In this report, the mechanism for the hypertriglyceridemia was studied. Two different HuCIIITg mouse lines were used: a low expressor line with serum triglycerides of approximately 280 mg/dl, and a high expressor line with serum triglycerides of approximately 1,000 mg/dl. Elevated triglycerides were mainly in VLDL. VLDL particles were 1.5 times more triglyceride-rich in high expressor mice than in controls. The total amount of apo CIII (human and mouse) per VLDL particle was 2 and 2.5 times the normal amount in low and high expressors, respectively. Mouse apo E was decreased by 35 and 77% in low and high expressor mice, respectively. Under electron microscopy, VLDL particles from low and high expressor mice were found to have a larger mean diameter, 55.2 +/- 16.6 and 58.2 +/- 17.8 nm, respectively, compared with 51.0 +/- 13.4 nm from control mice. In in vivo studies, radiolabeled VLDL fractional catabolic rate (FCR) was reduced in low and high expressor mice to 2.58 and 0.77 pools/h, respectively, compared with 7.67 pools/h in controls, with no significant differences in the VLDL production rates. In an attempt to explain the reduced VLDL FCR in transgenic mice, tissue lipoprotein lipase (LPL) activity was determined in control and high expressor mice and no differences were observed. Also, VLDLs obtained from control and high expressor mice were found to be equally good substrates for purified LPL. Thus excess apo CIII in HuCIIITg mice does not cause reduced VLDL FCR by suppressing the amount of extractable LPL in tissues or making HuCIIITg VLDL a bad substrate for LPL. Tissue uptake of VLDL was studied in hepatoma cell cultures, and VLDL from transgenic mice was found to be taken up much more slowly than control VLDL (P < 0.0001), indicating that HuCIIITg VLDL is not well recognized by lipoprotein receptors. Additional in vivo studies with Triton-treated mice showed increased VLDL triglyceride, but not apo B, production in the HuCIIITg mice compared with controls. Tissue culture studies with primary hepatocytes showed a modest increase in triglyceride, but not apo B or total protein, secretion in high expressor mice compared with controls. In summary, hypertriglyceridemia in HuCIIITg mice appears to result primarily from decreased tissue uptake of triglyceride-rich particles from the circulation, which is most likely due to increased apo CIII and decreased apo E on VLDL particles. the HuCIIITg mouse appears to be a suitable animal model of primary familial hypertriglyceridemia, and these studies suggest a possible mechanism for this common lipoprotein disorder.

Animals↗
PubMed1991

Methylation changes in the apolipoprotein AI gene during embryonic development of the mouse.

We report here a detailed study of developmental changes in the methylation status of specific sites in a single-copy tissue-specific gene, from the germ cell through the early embryo to adult tissues. Two sites at the 5' end of the mouse apolipoprotein AI gene were unmethylated in the ovulated unfertilized oocytes and methylated in the sperm. In contrast, a third site, located upstream of the gene, was methylated and a CpG island within the gene was unmethylated in both oocyte and sperm. The methylated sites, regardless of maternal or paternal origin, underwent demethylation in the early embryo (8-16 cells) and stayed unmethylated through the late blastocyst stage. During gastrulation, non-CpG island sites underwent methylation, followed by gradual demethylation at specific sites in tissues parallel to expression of the gene (liver and intestine). The formation of the mature tissue-specific methylation pattern of the apolipoprotein AI gene, therefore, involves the following three major events: (i) erasure of the germ-cell methylation pattern (at the 8- to 16-cell stage), (ii) formation of a new methylation pattern by de novo methylation of non-CpG island sites (during gastrulation), and (iii) tissue-specific demethylation associated with the onset of expression of the gene.

Aging↗
PubMed1991

Methylation patterns of the human apoA-I/C-III/A-IV gene cluster in adult and embryonic tissues suggest dynamic changes in methylation during development.

We describe here a detailed analysis of the methylation patterns of the apoC-III and apoA-IV genes in adult and embryonic tissues. Together with previously reported data on the human apoA-I gene (4), the results presented here constitute a comprehensive study on the methylation pattern of the apoA-I/C-III/A-IV gene cluster. The two genes (apoC-III and apoA-IV) display tissue-specific methylation patterns that correlate with their activity. This gene-specific methylation pattern indicates that the apoA-I/C-III/A-IV gene cluster is not one entity with respect to methylation. The cluster is almost entirely methylated in tissues that do not express any of the genes; however, individual gene regions are unmethylated in the tissue of expression. A comparison of the observed methylation patterns in adult tissues with those in embryonic tissues suggests that the mature tissue-specific methylation patterns are a result of an interplay between demethylation and de novo methylation events in the embryo. These changes in DNA methylation include demethylation in the early embryo followed by de novo methylation at later stages. A second round of tissue-specific demethylation and methylation de novo occurs in the late embryo as well. Evidence presented here supports the idea that CpG islands are protected in general from methylation de novo by a built-in signal and not by CpG density per se.

Adult↗
PubMed1991

Expression of the human apolipoprotein A-I gene in transgenic mice alters high density lipoprotein (HDL) particle size distribution and diminishes selective uptake of HDL cholesteryl esters.

Transgenic mice carrying the human apolipoprotein (apo) A-I gene (HuAITg mice) were used to examine the effects of overexpression of the human gene on high density lipoprotein (HDL) particle size distribution and metabolism. On a chow diet, control mice had HDL cholesterol and apo A-I levels of 49 +/- 2 and 137 +/- 12 mg/dl of plasma, respectively. HuAITg mice had HDL cholesterol, human apo A-I, and mouse apo A-I levels of 88 +/- 2, 255 +/- 19, and 16 +/- 2 mg/dl, respectively. Nondenaturing gradient gel electrophoresis revealed control mouse plasma HDL to be primarily monodisperse with a particle diameter of 10.2 nm, whereas HuAITg mouse plasma HDL was polydisperse with particles of diameter 11.4, 10.2, and 8.7 nm, which correspond in size to human HDL1, HDL2, and HDL3, respectively. In vivo turnover studies of HDL labeled with [3H]cholesteryl linoleyl ether (representing the cholesteryl ester pool) and 125I-apo A-I were performed. In control animals, the fractional catabolic rate (FCR) for HDL cholesteryl ester (0.197 +/- 0.010 pool/hr) was significantly (P less than 0.0005) more than the apo A-I FCR (0.118 +/- 0.006 pool/hr). In the HuAITg mice, the HDL cholesteryl ester FCR (0.124 +/- 0.008 pool/hr) was the same as the apo A-I FCR (0.126 +/- 0.010 pool/hr). There were no significant differences between control and HuAITg animals in the sites of tissue removal of HDL cholesteryl ester, with the liver extracting most of the injected radioactivity. Control and HuAITg animals had comparable liver and intestinal cholesterol synthesis and LDL FCR. In conclusion, HuAITg mice have principally human and not mouse apo A-I in their plasma. This apparently causes a change in HDL particle size distribution in the transgenic mice to one resembling the human pattern. The replacement of mouse by human apo A-I also apparently causes the loss of the selective uptake pathway of HDL cholesteryl esters present in control mice. These data imply that apo A-I primary structure has a profound influence on HDL particle size distribution and metabolism.

Adrenal Glands↗
PubMed1991

Plasma lipoprotein(a) concentration is controlled by apolipoprotein(a) (apo(a)) protein size and the abundance of hepatic apo(a) mRNA in a cynomolgus monkey model.

The cynomolgus macaque was used as a model to study lipoprotein(a) (Lp(a)). Antibodies to Lp(a) were used in Ouchterlony and Western blot analysis to show that cynomolgus monkey and human Lp(a) were similar immunochemically. Monkey Lp(a) levels were measured by a quantitative sandwich enzyme-linked immunosorbent assay in 117 animals, and Lp(a) varied in concentration from 1 to 64 mg/dl. Individual monkeys had apo(a) glycoprotein sizes as either single- or double-band phenotypes that ranged from 400 to 750 kDa. Monkey apo(a) transcript lengths varied from 8.5 to 13.6 kilobases. The Lp(a) concentration, apo(a) glycoprotein size, and apo(a) transcript length distributions were similar to those in humans. In the monkeys, there was a very high correlation between apo(a) transcript size and apo(a) protein size (R = 0.93, p = 0.0001). This variation in apo(a) transcript and protein size was shown to be due to the number of kringle IV repeats in apo(a) mRNA and DNA. Monkey plasma Lp(a) concentrations correlated inversely with apo(a) glycoprotein size (R = 0.43, p = 0.0016) and directly with hepatic apo(a) mRNA abundance (R = 0.54, p = 0.004). Apo(a) transcript lengths did not correlate with hepatic apo(a) mRNA levels. This suggests that apo(a) size and mRNA levels have major independent effects on plasma Lp(a) concentration. In multivariate analysis, they account for up to 58% of the variability in Lp(a) concentration. In summary, these data provide insight into the regulation of Lp(a) levels and suggest that the cynomolgus monkey is a suitable model in which to study the role of Lp(a) in the pathogenesis of atherosclerosis.

Animals↗
PubMed1991

Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer protein transgenic mice.

The human cholesteryl ester transfer protein (CETP) facilitates the exchange of neutral lipids among lipoproteins. In order to evaluate the effects of increased plasma CETP on lipoprotein levels, a human CETP minigene was placed under the control of the mouse metallothionein-I promoter and used to develop transgenic mice. Integration of the human CETP transgene into the mouse genome resulted in the production of active plasma CETP. Zinc induction of CETP transgene expression caused depression of serum cholesterol due to a significant reduction of high density lipoprotein cholesterol. There was no change in total cholesterol content in very low and low density lipoproteins. However, there was a decrease in the free cholesterol/cholesteryl ester ratio in plasma and in all lipoprotein fractions of transgenic mouse plasma, suggesting stimulation of plasma cholesterol esterification. The results suggest that high levels of plasma CETP activity may be a cause of reduced high density lipoproteins in humans.

Animals↗
PubMed1991

Apolipoprotein E gene expression in mouse 3T3-L1 adipocytes and human adipose tissue and its regulation by differentiation and lipid content.

Apolipoprotein E (apoE) is an important constituent of plasma lipoproteins and a ligand for several lipoprotein receptors. It is produced mainly in the liver but also in several peripheral tissues like brain, adrenal glands, kidney, and macrophages. Some of these tissues also coexpress lipoprotein lipase (LPL), an important enzyme in the metabolism of lipids and lipoproteins. This suggested a possible coordinate expression of these genes and led us to analyze whether adipocytes, a major source of LPL, could also synthesize apoE. Northern blotting experiments showed that apoE mRNA is found in differentiated mouse 3T3-L1 adipocytes as well as biopsies of human adipose tissue maintained in organ culture but not in undifferentiated 3T3-L1 preadipocytes. [35S]Methionine pulse-labeling experiments revealed that apoE protein is produced in human adipose tissue and differentiated mouse 3T3-L1 adipocytes but not in preadipocytes. In biosynthetic labeling experiments, most apoE was found to be cell associated even after prolonged chase periods. Heparin treatment of the cultured cells did not enhance apoE secretion. During differentiation of 3T3-L1 cells, the onset of apoE gene expression was later than that of LPL. The apoE mRNA and intracellular apoE protein concentrations increased linearly with time of differentiation, at least through day 11, whereas LPL showed highest expression at day 7 and then declined. The increase in apoE mRNA correlated with the cellular lipid content. Inhibition of lipid accumulation in differentiated cells by biotin deprivation decreased apoE expression. Cholesterol-loading experiments suggested that apoE mRNA expression is regulated by the intracellular free cholesterol content of 3T3-L1 adipocytes. In contrast, the LPL mRNA level was not influenced by biotin deprivation or cholesterol loading. Human recombinant tumor necrosis factor, a potent inhibitor of LPL gene transcription, had no effect on adipocyte apoE mRNA levels. Therefore, although apoE and LPL are both expressed in adipocytes in a differentiation-dependent manner, the time course of their expression differs as do their responses to cellular lipid content and tumor necrosis factor. We conclude that these genes are not coordinately regulated in adipocytes.

Adipose Tissue↗
PubMed1991

Lovastatin efficacy in reducing low-density lipoprotein cholesterol levels on high- vs low-fat diets.

The effectiveness of lovastatin was compared with both a high-fat vs low-fat diet. Hypercholesterolemic subjects were studied under metabolic ward conditions for diet periods of 3 weeks while receiving lovastatin (40 mg/d) or placebo. Multiple lipoprotein levels were measured during the final week of each diet period. Nineteen subjects completed the study on the high-fat (43% of kilojoules) diet and 16 on the low-fat (25% of kilojoules) diet. Lovastatin reduced total cholesterol by 23% and low-density lipoprotein cholesterol by 30%, compared with placebo on both diets, with no significant diet-drug interaction. High-density lipoprotein cholesterol was raised by 7% to 8% on the diet regimens. Addition of lovastatin to the low-fat diet permitted 80% of subjects on this diet, but less than 50% of those on the high-fat diet, to achieve current guidelines. Although lovastatin produces a comparable percentage reduction in lipoprotein profiles on either diet, the accompanying low-fat diet remains advisable for additional reduction of low-density lipoprotein cholesterol levels to specified goals.

Apolipoproteins↗
PubMed1991

Lipoprotein(a) reduction by N-acetylcysteine.

Lipoprotein(a), a complex of low-density lipoprotein linked by disulphide bridges with apo(a), is associated with atherosclerotic disease when present at very high plasma concentrations. In vitro, N-acetylcysteine (NAC) dissociates this complex. In two patients with high Lp(a) levels NAC lowered plasma Lp(a) from 58 to 20 mg/dl and from 59 to 18 mg/dl: reductions of this order have not hitherto been achieved either by drugs or by diet.

Acetylcysteine↗