Cholesterol Metabolism Genes Research Articles

Expression of intercellular lipid transport and cholesterol metabolism genes in eggs and early larvae stages of turbot, Scophthalmus maximus, a marine aquaculture species

Growth and energy transfer are critically dependent on effective transport of lipid molecules between tissues and cellular compartments. This process is specific in egg and eleutheroembryos, when energetic and structural lipids, located at the yolk sac, need to be mobilized in order to be incorporated in the new forming embryo, or to produce energy. Here, we describe the transcriptional profile of 11 genes that codify for proteins involved in intercellular lipid transport and cholesterol metabolism during the early development of a marine teleost fish (Scophthalmus maximus), from notochord formation to the period beyond mouth opening. The mRNA expression pattern of genes (apoA1, apoB100, apoE, cetp, mtp, pltp, lipC, lpl, hmgcr1, soat1, lcat) is described and related to previously published lipid levels in larvae and PPARs—peroxisome proliferator-activated receptors—mRNA levels from the same experiment (Cunha et al. in Mar Genomics 10:17–25, 2013). Our findings show that the transcription of genes responsible for apolipoproteins production starts soon before hatching and that activities decline along the development. In contrast, genes responsible for cholesterol synthesis have a low transcription level early in the development and their activity increases later. Apolipoproteins and other genes related to reverse cholesterol transport are possibly under the control of Pparα2, while the expression of extracellular lipid transfer proteins and enzymes involved in cholesterol synthesis is possibly under the simultaneous control of Pparα1 and Pparγ. Generally, the observed transcription of genes involved in lipid transport is in accordance with the lipid composition of the larvae and transcription of master regulators of lipid metabolism such as the nuclear receptors—PPARs.

Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease.

Obesity is linked to type 2 diabetes (T2D) and cardiovascular diseases; however, the underlying molecular mechanisms remain unclear. We aimed to identify obesity-associated molecular features that may contribute to obesity-related diseases. Using circulating monocytes from 1,264 Multi-Ethnic Study of Atherosclerosis (MESA) participants, we quantified the transcriptome and epigenome. We discovered that alterations in a network of coexpressed cholesterol metabolism genes are a signature feature of obesity and inflammatory stress. This network included 11 BMI-associated genes related to sterol uptake (↑LDLR, ↓MYLIP), synthesis (↑SCD, FADS1, HMGCS1, FDFT1, SQLE, CYP51A1, SC4MOL), and efflux (↓ABCA1, ABCG1), producing a molecular profile expected to increase intracellular cholesterol. Importantly, these alterations were associated with T2D and coronary artery calcium (CAC), independent from cardiometabolic factors, including serum lipid profiles. This network mediated the associations between obesity and T2D/CAC. Several genes in the network harbored C-phosphorus-G dinucleotides (e.g., ABCG1/cg06500161), which overlapped Encyclopedia of DNA Elements (ENCODE)-annotated regulatory regions and had methylation profiles that mediated the associations between BMI/inflammation and expression of their cognate genes. Taken together with several lines of previous experimental evidence, these data suggest that alterations of the cholesterol metabolism gene network represent a molecular link between obesity/inflammation and T2D/CAC.

Effect of testosterone deficiency on cholesterol metabolism in pigs fed a high-fat and high-cholesterol diet.

BackgroundTestosterone deficiency is associated with increased serum cholesterol levels. However, how testosterone deficiency precisely affects cholesterol metabolism remains unclear. Therefore, in the current study, we examined the effect of testosterone deficiency on cholesterol metabolism and liver gene expression in pigs fed a high-fat and high-cholesterol (HFC) diet.MethodsSexually mature male miniature pigs (6–7 months old) were randomly divided into 3 groups as follows: intact male pigs fed an HFC diet (IM + HFC), castrated male pigs fed an HFC diet (CM + HFC), and castrated pigs with testosterone replacement fed an HFC diet (CM + HFC + T). Serum testosterone levels and lipid profiles were measured, and gene expression levels associated with hepatic cholesterol metabolism were determined. Furthermore, total hepatic cholesterol contents and the activities of enzymes mediating hepatic cholesterol metabolism were measured.ResultsSerum testosterone levels were significantly decreased in CM + HFC pigs, and testosterone replacement attenuated castration-induced testosterone deficiency. Castration significantly increased the serum levels of total cholesterol, low-density lipoprotein cholesterol and triglycerides, as well as hepatic lipid contents in pigs fed an HFC diet. Compared with IM + HFC and CM + HFC + T pigs, low-density lipoprotein receptor (LDLR) mRNA expression and protein levels were significantly decreased in the livers of CM + HFC pigs. In contrast, we found that compared with IM + HFC pigs, hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and serum PCSK9 protein levels were significantly increased in CM + HFC pigs. Moreover, testosterone treatment reversed the increase in PCSK9 expression in CM + HFC pigs. However, neither castration nor testosterone replacement affected the expression of the other hepatic genes that were tested.ConclusionsThis study demonstrated that castration-induced testosterone deficiency caused severe hypercholesterolemia in pigs fed an HFC diet; furthermore, these effects could be reversed by testosterone replacement therapy. Altered hepatic PCSK9 and LDLR expression, resulting in reduced LDL-cholesterol clearance, may contribute to the increased serum cholesterol levels induced by testosterone deficiency and an HFC diet. These results deepen our understanding of the underlying molecular mechanisms that mediate the effects of testosterone deficiency on cholesterol metabolism.

Cholesterol metabolism and prostate cancer-specific mortality.

12 Background: Cholesterol is needed in prostate cancer cells for cell proliferation and for androgen biosynthesis. Cholesterol-lowering statin drug use is associated with a lower risk of total and advanced prostate cancer and lower prostate cancer-specific mortality (PCSM). We hypothesized that tumor expression of cholesterol synthesis enzymes, transporters and regulators is associated with PCSM. Methods: We studied mRNA expression of 43 cholesterol metabolism genes in surgical specimens from 249 participants in the Health Professionals' Follow-up Study diagnosed with prostate cancer between 1986 and 2004. We included 81 cases of lethal prostate cancer and 168 indolent cases who survived >8 years without metastases. After multivariate dimensionality reduction for the synthesis, transport and regulator pathways using principal components analysis, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. We adjusted for age, year of diagnosis, body mass index, smoking status, family history, multivitamin use, high serum cholesterol and cholesterol-lowering drug use. Results: Reflecting the impact of the synthesis pathway and of the regulator pathway, respectively, the expression of squalene epoxidase (SQLE) and low-density lipoprotein receptor (LDLR) were significantly associated with lethal cancer in opposing directions. Compared to men with the mean level of SQLE expression, men with SQLE expression >1 standard deviation (SD) above the mean were 15.4 times more likely to have lethal cancer (95% CI: 3.31–71.53). For LDLR, expression >1 SD above the mean was associated with 96% lower odds of lethal cancer (95% CI: 0.01–0.70). Higher SQLE expression and lower LDLR expression were associated with higher Gleason grades (Fisher's test, p < 0.001 and p = 0.036, respectively) and were also predictive of PCSM independently from grade and tumor stage. Conclusions: These results suggest that the local cholesterol metabolism of the prostate tumor is tightly linked with mortality. Lethal cancers have higher activity of the second rate-controlling enzyme of cholesterol synthesis and are less dependent on cholesterol uptake.

Antihypercholesterolemic Effects of Mushroom, Chrysin, Curcumin and Omega-3 in Experimental Hypercholesterolemic Rats

Hypercholesterolemia and hypertriglyceridemia are major risk factors that accelerate the incidence of atherosclerosis and coronary artery diseases. Therefore, the present study was conducted to evaluate the hypolipidemic effect of widely known traditional medicinal herbs and omega-3 FA in experimental hypercholesterolemia induced by Triton WR-1339. Experimental hypercholesterolemic rats were administered mushroom, chrysin, curcumin and omega-3 for 2 weeks. Hypercholesterolemic rats showed an increase in serum levels of lipid profiles and hepatic enzymes. Hypercholesterolemic rats showed an increase in malondialdehyde (MDA) levels and a decrease in both serum levels and mRNA expression of catalase, superoxide dismutase (SOD) and glutathione reducatse. Moreover, hypercholesterolemic rats showed hepatic down regulation in the expression of genes related to fatty acids oxidation such as acyl CoA oxidase (ACO) and synthetase (ACS), together with carnityl palmityl transferase-1 (CPT-1) and peroxisome proliferator activator receptor-α (PPAR-α). Administration of mushroom, chrysin, curcumin and omega-3 to hypercholesterolemic rats for 2 weeks up-regulated significantly the down regulated genes. In contrast, expression of genes related to fatty acids biosynthesis and cholesterol metabolism were increased in hypercholesterolemic rats compared to control group. Herbal medications and omega-3 administration down regulated genes of fatty acids biosynthesis and cholesterol metabolism to normal expression. At cellular levels, hyperlipidemia induced fatty droplets accumulation, necrosis and presence of apoptotic hepatocytes together with leukocytic infiltration in necrotic area that are ameliorated and normalized after administration of herbs and omega-3. In conclusion, the current findings indicated that flavonoids (mushroom, chrysin, curcumin) and omega-3 possess antihypercholesterolemic effects at biochemical, molecular and histopathological levels and are useful in treatment of hypercholesterolemia with lower side effects compared with synthetic hypolipidemic drugs.

SREBP maintains lipid biosynthesis and viability of cancer cells under lipid- and oxygen-deprived conditions and defines a gene signature associated with poor survival in glioblastoma multiforme.

Oxygen and nutrient limitation are common features of the tumor microenvironment and are associated with cancer progression and induction of metastasis. The inefficient vascularization of tumor tissue also limits the penetration of other serum-derived factors, such as lipids and lipoproteins, which can be rate limiting for cell proliferation and survival. Here we have investigated the effect of hypoxia and serum deprivation on sterol regulatory element-binding protein (SREBP) activity and the expression of lipid metabolism genes in human glioblastoma multiforme (GBM) cancer cells. We found that SREBP transcriptional activity was induced by serum depletion both in normoxic and hypoxic cells and that activation of SREBP was required to maintain the expression of fatty acid and cholesterol metabolism genes under hypoxic conditions. Moreover, expression of stearoyl-CoA desaturase, the enzyme required for the generation of mono-unsaturated fatty acids, and fatty acid-binding protein 7, a regulator of glioma stem cell function, was strongly dependent on SREBP function. Inhibition of SREBP function blocked lipid biosynthesis in hypoxic cancer cells and impaired cell survival under hypoxia and in a three-dimensional spheroid model. Finally, gene expression analysis revealed that SREBP defines a gene signature that is associated with poor survival in glioblastoma.

Sex specific response in cholesterol level in zebrafish (Danio rerio) after long-term exposure of difenoconazole

Difenoconazole is a widely used triazole fungicide, its extensive application may potentially cause toxic effects on non-target organisms. To investigate the effect of difenoconazole on cholesterol content and related mechanism, adult zebrafish were exposed to environmental related dosage (0.1, 10 and 500 μg/L) difenoconazole. The body weight and hepatic total cholesterol (TCHO) level was tested at 7, 15 and 30 days post exposure (dpe). The expressions of eight cholesterol synthesis genes and one cholesterol metabolism gene were assessed via Quantitative PCR method. The significant decrease of TCHO level in male zebrafish liver was observed at 15 and 30 dpe, which was accompanied by apparent hepatic cholesterol-genesis genes expression decline. In comparison with males, female zebrafish showed different transcription modification of tested genes, and the cholesterol content maintain normal level during the whole exposure.

TET1 regulates hypoxia-induced epithelial-mesenchymal transition by acting as a co-activator.

BackgroundHypoxia induces the epithelial-mesenchymal transition, EMT, to promote cancer metastasis. In addition to transcriptional regulation mediated by hypoxia-inducible factors, HIFs, other epigenetic mechanisms of gene regulation, such as histone modifications and DNA methylation, are utilized under hypoxia. However, whether DNA demethylation mediated by TET1, a DNA dioxygenase converting 5-methylcytosine, 5mC, into 5-hydroxymethylcytosine, 5hmC, plays a role in hypoxia-induced EMT is largely unknown.ResultsWe show that TET1 regulates hypoxia-responsive gene expression. Hypoxia/HIF-2α regulates the expression of TET1. Knockdown of TET1 mitigates hypoxia-induced EMT. RNA sequencing and 5hmC sequencing identified the set of TET1-regulated genes. Cholesterol metabolic process genes are among the genes that showed high prevalence and statistical significance. We characterize one of the genes, INSIG1 (insulin induced gene 1), to confirm its expression and the 5hmC levels in its promoter. Knockdown of INSIG1 also mitigates hypoxia-induced EMT. Finally, TET1 is shown to be a transcriptional co-activator that interacts with HIF-1α and HIF-2α to enhance their transactivation activity independent of its enzymatic activity. TET1 acts as a co-activator to further enhance the expression of INSIG1 together with HIF-2α. We define the domain in HIF-1α that interacts with TET1 and map the domain in TET1 that confers transactivation to a 200 amino acid region that contains a CXXC domain. The TET1 catalytically inactive mutant is capable of rescuing hypoxia-induced EMT in TET1 knockdown cells.ConclusionsThese findings demonstrate that TET1 serves as a transcription co-activator to regulate hypoxia-responsive gene expression and EMT, in addition to its role in demethylating 5mC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0513-0) contains supplementary material, which is available to authorized users.

Successful validation of genomic biomarkers for human immunotoxicity in Jurkat T cells in vitro

Previously, we identified 25 classifier genes that were able to assess immunotoxicity using human Jurkat T cells. The present study aimed to validate these classifiers. For that purpose, Jurkat cells were exposed for 6 h to subcytotoxic doses of nine immunotoxicants, five non-immunotoxicants and four compounds for which human immunotoxicity has not yet been fully established. RNA was isolated and subjected to Fluidigm quantitative real time (qRT)-PCR analysis. The sensitivity, specificity and accuracy of the screening assay as based on the nine immunotoxicants and five non-immunotoxicants used in this study were 100%, 80% and 93%, respectively, which is better than the performance in our previous study. Only one compound was classified as false positive (benzo-e-pyrene). Of the four potential (non-)immunotoxicants, chlorantraniliprole and Hidrasec were classified immunotoxic and Sunset yellow and imidacloprid as non-immunotoxic. ToxPi analysis of the PCR data provided insight in the molecular pathways that were affected by the compounds. The immunotoxicants 2,3-dichloro-propanol and cypermethrin, although structurally different, affected protein metabolism and cholesterol biosynthesis and transport. In addition, four compounds, i.e. chlorpyrifos, aldicarb, benzo-e-pyrene and anti-CD3, affected genes in cholesterol metabolism and transport, protein metabolism and transcription regulation. qRT-PCR on eight additional genes coding for similar processes as defined in ToxPi analyzes, supported these results. In conclusion, the 25 immunotoxic classifiers performed very well in a screening with new non-immunotoxic and immunotoxic compounds. Therefore, the Jurkat screening assay has great promise to be applied within a tiered approach for animal free testing of human immunotoxicity.

The intake of a high-fat diet and grape seed procyanidins induces gene expression changes in peripheral blood mononuclear cells of hamsters: capturing alterations in lipid and cholesterol metabolisms.

We previously demonstrated that hamsters that were fed either a standard diet (STD) or a high-fat diet (HFD) and treated with a grape seed procyanidin extract (GSPE) showed decreased adiposity and circulating levels of free fatty acids compared with hamsters treated with a vehicle (Caimari et al. in Int J Obes 37:576-83, 2013, doi: 10.1038/ijo.2012.75 ). Here, we tested whether the gene expression changes in peripheral blood mononuclear cells (PBMCs) can reflect these metabolic effects and the dyslipidaemia produced by the HFD feeding in the same cohort of animals. The mRNA levels of a subset of genes were also studied in the liver in order to evaluate the capacity of PBMCs to reflect the metabolic adaptations that occur in this organ. In PBMCs, we reported a simultaneous up-regulation of the lipid-related genes involved in both the anabolic (pparγ, acc1 and gpat) and the catabolic (pparα, ucp2, atgl and hsl) pathways in response to the GSPE treatment, similar but no identical to previous observations in retroperitoneal white adipose tissues of these animals. Furthermore, the key cholesterol metabolism genes srebp2 and ldlr were significantly down-regulated in PBMCs of both HFD-fed groups compared with the STD groups. Although the expression of srebp2 in the liver followed a similar pattern to that obtained in PBMCs, no comparable changes were found between the liver and PBMCs in the expression of most of the studied genes. In conclusion, our results highlight the potential of PBMCs as a high accessible tissue for the indirect study of cholesterol and adipose tissue metabolism dynamics.

Maternal dietary betaine supplementation modifies hepatic expression of cholesterol metabolic genes via epigenetic mechanisms in newborn piglets.

To elucidate the effects of maternal dietary betaine supplementation on hepatic expression of cholesterol metabolic genes in newborn piglets and the involved epigenetic mechanisms, we fed gestational sows with control or betaine-supplemented diets (3g/kg) throughout pregnancy. Neonatal piglets born to betaine-supplemented sows had higher serum methionine concentration and hepatic content of betaine, which was associated with significantly up-regulated hepatic expression of glycine N-methyltransferase. Prenatal betaine exposure increased hepatic cholesterol content and modified the hepatic expression of cholesterol metabolic genes in neonatal piglets. Sterol regulatory element-binding protein 2 was down-regulated at both mRNA and protein levels, while 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) was down-regulated at the mRNA level, but up-regulated at the protein level, in betaine-exposed piglets. The transcriptional repression of HMGCR was associated with CpG island hypermethylation and higher repressive histone mark H3K27me3 (histone H3 lysine 27 trimethylation) on the promoter, whereas increased HMGCR protein content was associated with significantly decreased expression of miR-497. Furthermore, LDL receptor was significantly down-regulated at both mRNA and protein levels in the liver of betaine-exposed piglets, which was associated with promoter CpG hypermethylation. In addition, the expression of cholesterol-27α-hydroxylase (CYP27α1) was up-regulated at both mRNA and protein levels, while the expression of cholesterol-7α-hydroxylase (CYP7α1) was increased at the mRNA level, but unchanged at the protein level associated with increased expression of miR-181. These results indicate that maternal betaine supplementation increases hepatic cholesterol content in neonatal piglets through epigenetic regulations of cholesterol metabolic genes, which involve alterations in DNA and histone methylation and in the expression of microRNA targeting these genes.

Variation in cholesterol absorption in healthy male adults can be explained by a combination of SNPs in cholesterol metabolism genes

Objectives: Blood cholesterol concentration is positively associated with atherosclerosis and cardiovascular disease risk. Cholesterol absorption efficiency displays a high inter-individual variability that is assumed to be due to both dietary and genetic factors. Several polymorphisms have been identified but existing studies have so far focused on single SNPs that only explained a minor fraction of the variability of such a complex phenotype. This study thus aimed to identify a combination of SNPs that could explain a significant part of the variability in cholesterol absorption efficiency.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Thyroid hormone induction of human cholesterol 7 alpha-hydroxylase (Cyp7a1) in vitro

Thyroid hormone (TH) modulates serum cholesterol by acting on TH receptor β1 (TRβ1) in liver to regulate metabolic gene sets. In rodents, one important TH regulated step involves induction of Cyp7a1, an enzyme in the cytochrome P450 family, which enhances cholesterol to bile acid conversion and plays a crucial role in regulation of serum cholesterol levels. Current models suggest, however, that Cyp7a1 has lost the capacity to respond to THs in humans. We were prompted to re-examine TH effects on cholesterol metabolic genes in human liver cells by a recent study of a synthetic TH mimetic which showed that serum cholesterol reductions were accompanied by increases in a marker for bile acid synthesis in humans. Here, we show that TH effects upon cholesterol metabolic genes are almost identical in mouse liver, mouse and human liver primary cells and human hepatocyte cell lines. Moreover, Cyp7a1 is a direct TR target gene that responds to physiologic TR levels through a set of distinct response elements in its promoter. These findings suggest that THs regulate cholesterol to bile acid conversion in similar ways in humans and rodent experimental models and that manipulation of hormone signaling pathways could provide a strategy to enhance Cyp7a1 activity in human patients.

Complete Genome Sequence of Sterol-Transforming Mycobacterium neoaurum Strain VKM Ac-1815D

Mycobacterium neoaurum strain VKM Ac-1815D produces 4-androstene-3,17-dione as a major compound from phytosterols. Here, we report the complete genome sequence of the strain. The genome consists of a single circular 5,438,190-bp chromosome, with a G+C content of 66.88%, containing 5,318 putative open reading frames (ORFs), 46 tRNAs, and 6 rRNAs. Arrays of cholesterol metabolism genes are randomly clustered throughout the chromosome.

Recipient perioperative cholesterolaemia and graft cholesterol metabolism gene expression predict liver transplant outcome

We analysed for the first time whether recipient perioperative serum total cholesterol (sTC) concentration is associated with liver transplantation outcome. We studied noncholestatic cirrhotics submitted to primary deceased-donor liver transplantation in a prospective group (n=140) from Rome and in a validation retrospective cohort (n=157) from Udine, Italy. Pre-ischaemia and post-reperfusion cholesterol metabolism gene mRNA was measured by RT-PCR in 74 grafts of the study group. At Cox regression analysis, independently from confounders including recipient MELD score, the recipient pre-operative sTC pooled quintiles 2-5, compared with the lowest quintile showed HR (95% CI) and significances for overall graft loss (GL) of 0.215 (0.104-0.444) P<0.001 in the study group and 0.319 (0.167-0.610) P=0.001 in the validation cohort. Analysing sTC as a continuous variable, the risk of overall GL for every 10-mg/dl decrease in pre-operative sTC increased by 13% and by 9% in the study group and in the validation cohort respectively. In the study group, independent associations at multivariate analyses were: (a) high graft pre-ischaemia expression of INSIG-1, which indicates hepatocellular cholesterol depletion, with post-reperfusion graft necrosis; (b) GL with inadequate graft post-reperfusion response to cholesterol depletion, shown by a failure to reduce the PCSK9 to LDLR expression ratio; (c) GL with a relative increase of sTC on post-operative day-7, selectively because of the LDL fraction, which indirectly suggests poor cholesterol uptake from blood. Low recipient pre-transplant sTC concentration, its post-operative day-7 increase and a genetically determined low graft cholesterol availability predict poor liver transplant outcome.

Conservation of lipid metabolic gene transcriptional regulatory networks in fish and mammals

Lipid content and composition in aquafeeds have changed rapidly as a result of the recent drive to replace ecologically limited marine ingredients, fishmeal and fish oil (FO). Terrestrial plant products are the most economic and sustainable alternative; however, plant meals and oils are devoid of physiologically important cholesterol and long-chain polyunsaturated fatty acids (LC-PUFA), eicosapentaenoic (EPA), docosahexaenoic (DHA) and arachidonic (ARA) acids. Although replacement of dietary FO with vegetable oil (VO) has little effect on growth in Atlantic salmon (Salmo salar), several studies have shown major effects on the activity and expression of genes involved in lipid homeostasis. In vertebrates, sterols and LC-PUFA play crucial roles in lipid metabolism by direct interaction with lipid-sensing transcription factors (TFs) and consequent regulation of target genes. The primary aim of the present study was to elucidate the role of key TFs in the transcriptional regulation of lipid metabolism in fish by transfection and overexpression of TFs. The results show that the expression of genes of LC-PUFA biosynthesis (elovl and fads2) and cholesterol metabolism (abca1) are regulated by Lxr and Srebp TFs in salmon, indicating highly conserved regulatory mechanism across vertebrates. In addition, srebp1 and srebp2 mRNA respond to replacement of dietary FO with VO. Thus, Atlantic salmon adjust lipid metabolism in response to dietary lipid composition through the transcriptional regulation of gene expression. It may be possible to further increase efficient and effective use of sustainable alternatives to marine products in aquaculture by considering these important molecular interactions when formulating diets.

Genetic and transcriptomic studies of PFOA and PFOS: thyroid hormones, lipid metabolism and transporter proteins

Background: Cross sectional analyses of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) in exposed human populations show associations with serum cholesterol and thyroid hormones. Expression studies in relevant genes can provide supportive evidence for the biological activity of these compounds. Large variability in observed half life of these compounds may have a genetic component, in particular in relation to transporter proteins, such as organic anion transporters (OAT). Objectives: To assess the association of PFOA or PFOS exposure on the expression of genes related to cholesterol and thyroid hormone metabolism or transport, and the association of polymorphisms in transporter genes with PFOA and PFOS excretion half-life. Methods: In 2010 we took blood samples from adult volunteers in the C8 Science Panel study in the Mid-Ohio Valley, 755 for the polymorphisms analysis and 400 for the gene expression studies. We measured PFOA and PFOS levels at both 2005/6 and 2010. RNA samples were extracted for gene expression. The transcript expression of a panel of 12 lipid metabolism genes and 5 thyroid hormone synthesis or thyroid receptor genes was tested by quantitative real-time PCR, and regressed on serum PFOA or PFOS. Individual half-lives were estimated from falls in serum levels of PFOA and PFOS from samples collected in 2010-11 and 2005-06. GoldenGate chemistry was used to genotype single nucleotide polymorphisms in candidate transporter genes. Genotype distributions and allele frequencies were calculated, and the relations were assessed by logistic regression between genotypes and serum half-lives, controlling for potential confounders. Results: Among cholesterol metabolism and transport genes, expression was associated with serum PFOA for NR1H2, NPC1 and ABCG1 genes and with PFOS for NCEH1. Thyroid gene analyses are ongoing. Among all the polymorphisms in OAT genes considered, the strongest effect was the drop in PFOA was 28% steeper with a specific variant of OAT3.

Interaction Between Two Cholesterol Metabolism Genes Influences Memory: Findings from the Wisconsin Registry for Alzheimer's Prevention

The strongest genetic factor for late-onset Alzheimer's disease (AD) is APOE; nine additional susceptibility genes have recently been identified. The effect of these genes is often assumed to be additive and polygenic scores are formed as a summary measure of risk. However, interactions between these genes are likely to be important. We sought to examine the role of interactions between the nine recently identified AD susceptibility genes and APOE in cognitive function and decline in 1,153 participants from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of middle-aged adults enriched for a parental history of AD. Participants underwent extensive cognitive testing at baseline and up to two additional visits approximately 4 and 6 years later. The influence of the interaction between APOE and each of 14 single nucleotide polymorphisms (SNPs) in the nine recently identified genes on three cognitive factor scores (Verbal Learning and Memory, Working Memory, and Immediate Memory) was examined using linear mixed models adjusting for age, gender, and ancestry. Interactions between the APOE ε4 allele and both of the genotyped ABCA7 SNPs, rs3764650 and rs3752246, were associated with all three cognitive factor scores (p-values ≤ 0.01). Both of these genes are in the cholesterol metabolism pathway leading to AD. This research supports the importance of considering non-additive effects of AD susceptibility genes.

Diet supplementation with beta-carotene improves the serum lipid profile in rats fed a cholesterol-enriched diet

The present study investigated the underlying mechanism associated with the hypocholesterolemic activity of beta-carotene by examining its effects on the serum lipid profile, fecal cholesterol excretion, and gene expression of the major receptors, enzymes, and transporters involved in cholesterol metabolism. Female Fischer rats were divided into three groups and were fed either a control or a hypercholesterolemic diet supplemented or not supplemented with 0.2 % beta-carotene. After 6 weeks of feeding, blood, livers, and feces were collected for analysis, and quantitative real-time polymerase chain reaction (qRT-PCR) was performed. Dietary supplementation with 0.2 % beta-carotene decreased serum total cholesterol, non-HDL cholesterol, the atherogenic index, and hepatic total lipid and cholesterol contents. These changes were accompanied by an increase in the total lipid and cholesterol contents excreted in the feces. The qRT-PCR analyses demonstrated that the hypercholesterolemic diet promoted a decrease in the gene expression of sterol regulatory element-binding protein 2, 3-hydroxy-3-methylglutaryl CoA reductase, and low-density lipoprotein receptor and an increase in the gene expression of peroxisome proliferator-activated receptor α and cholesterol-7a-hydroxylase. The expression of these genes and gene expression of ATP-binding cassette subfamily G transporters 5and 8 were unaffected by beta-carotene supplementation. In conclusion, the decrease in serum cholesterol and the elevation of fecal cholesterol obtained following beta-carotene administration indicate that this substance may decrease cholesterol absorption in the intestine and increase cholesterol excretion into the feces without a direct effect on the expression of cholesterol metabolism genes.