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Regulatory MicroRNAs in Aberrant Cholesterol Transport and Metabolism

Posted in Atherogenic Processes & Pathology, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cardiovascular Tissue, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Lipid metabolism, mRNA Therapeutics, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Origins of Cardiovascular Disease, PCSK9 Inhibitor Therapy, Pharmacotherapy of Cardiovascular Disease, tagged Atherosclerosis, Atherosclerotic Cardiovascular Disease, HDL-cholesterol, LDL cholesterol, microRNAs on March 4, 2017| Leave a Comment »

Regulatory MicroRNAs in Aberrant Cholesterol Transport and Metabolism

Curator: Marzan Khan, B.Sc

Aberrant levels of lipids and cholesterol accumulation in the body lead to cardiometabolic disorders such as atherosclerosis, one of the leading causes of death in the Western World(1). The physical manifestation of this condition is the build-up of plaque along the arterial endothelium causing the arteries to constrict and resist a smooth blood flow(2). This obstructive deposition of plaque is merely the initiation of atherosclerosis and is enriched in LDL cholesterol (LDL-C) as well foam cells which are macrophages carrying an overload of toxic, oxidized LDL(2). As the condition progresses, the plaque further obstructs blood flow and creates blood clots, ultimately leading to myocardial infarction, stroke and other cardiovascular diseases(2). Therefore, LDL is referred to as “the bad cholesterol”(2).

Until now, statins are most widely prescribed as lipid-lowering drugs that inhibit the enzyme 3-hydroxy-3methylgutaryl-CoA reductase (HMGCR), the rate-limiting step in de-novo cholesterol biogenesis (1). But some people cannot continue with the medication due to it’s harmful side-effects(1). With the need to develop newer therapeutics to combat cardiovascular diseases, Harvard University researchers at Massachusetts General Hospital discovered 4 microRNAs that control cholesterol, triglyceride, and glucose homeostasis(3)

MicroRNAs are non-coding, regulatory elements approximately 22 nucleotides long, with the ability to control post-transcriptional expression of genes(3). The liver is the center for carbohydrate and lipid metabolism. Stringent regulation of endogenous LDL-receptor (LDL-R) pathway in the liver is crucial to maintain a minimal concentration of LDL particles in blood(3). A mechanism whereby peripheral tissues and macrophages can get rid of their excess LDL is mediated by ATP-binding cassette, subfamily A, member 1 (ABCA1)(3). ABCA1 consumes nascent HDL particles- dubbed as the “good cholesterol” which travel back to the liver for its contents of triglycerides and cholesterol to be excreted(3).

Genome-wide association studies (GWASs) meta-analysis carried out by the researchers disclosed 4 microRNAs –(miR-128-1, miR-148a, miR-130b, and miR-301b) to lie close to single-nucleotide polymorphisms (SNPs) associated with abnormal metabolism and transport of lipids and cholesterol(3) Experimental analyses carried out on relevant cell types such as the liver and macrophages have proven that these microRNAs bind to the 3’ UTRs of both LDL-R and ABCA1 transporters, and silence their activity. Overexpression of miR-128-1 and miR148a in mice models caused circulating HDL-C to drop. Corroborating the theory under investigation further, their inhibition led to an increased clearance of LDL from the blood and a greater accumulation in the liver(3).

That the antisense inhibition of miRNA-128-1 increased insulin signaling in mice, propels us to hypothesize that abnormal expression of miR-128-1 might cause insulin resistance in metabolic syndrome, and defective insulin signaling in hepatic steatosis and dyslipidemia(3)

Further examination of miR-148 established that Liver-X-Receptor (LXR) activation of the Sterol regulatory element-binding protein 1c (SREBP1c), the transcription factor responsible for controlling fatty acid production and glucose metabolism, also mediates the expression of miR-148a(4,5) That the promoter region of miR-148 contained binding sites for SREBP1c was shown by chromatin immunoprecipitation combined with massively parallel sequencing (ChIP-seq)(4). More specifically, SREBP1c attaches to the E-box2, E-box3 and E-box4 elements on miR-148-1a promoter sites to control its expression(4).

Earlier, the same researchers- Andres Naars and his team had found another microRNA called miR-33 to block HDL generation, and this blockage to reverse upon antisense targeting of miR-33(6).

These experimental data substantiate the theory of miRNAs being important regulators of lipoprotein receptors and transporter proteins as well as underscore the importance of employing antisense technologies to reverse their gene-silencing effects on LDL-R and ABCA1(4). Such a therapeutic approach, that will consequently lower LDL-C and promote HDL-C seems to be a promising strategy to treat atherosclerosis and other cardiovascular diseases(4).

References:

1.Goedeke L¹,Wagschal A²,Fernández-Hernando C³, Näär AM⁴. miRNA regulation of LDL-cholesterol metabolism. Biochim Biophys Acta. 2016 Dec;1861(12 Pt B):. Biochim Biophys Acta. 2016 Dec;1861(12 Pt B):2047-2052

https://www.ncbi.nlm.nih.gov/pubmed/26968099

2.MedicalNewsToday. Joseph Nordgvist. Atherosclerosis:Causes, Symptoms and Treatments. 13.08.2015

http://www.medicalnewstoday.com/articles/247837.php

3.Wagschal A^1,2, Najafi-Shoushtari SH^1,2, Wang L^1,2, Goedeke L³, Sinha S⁴, deLemos AS⁵, Black JC^1,6, Ramírez CM³, Li Y⁷, Tewhey R^8,9, Hatoum I¹⁰, Shah N¹¹, Lu Y¹¹, Kristo F¹, Psychogios N⁴, Vrbanac V¹², Lu YC¹³, Hla T¹³, de Cabo R¹⁴, Tsang JS¹¹, Schadt E¹⁵, Sabeti PC^8,9, Kathiresan S^4,6,8,16, Cohen DE⁷, Whetstine J^1,6, Chung RT^5,6, Fernández-Hernando C³, Kaplan LM^6,10, Bernards A^1,6,16, Gerszten RE^4,6, Näär AM^1,2. Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. . Nat Med.2015 Nov;21(11):1290

https://www.ncbi.nlm.nih.gov/pubmed/26501192

4.Goedeke L^1,2,3,4, Rotllan N^1,2, Canfrán-Duque A^1,2, Aranda JF^1,2,3, Ramírez CM^1,2, Araldi E^1,2,3,4, Lin CS^3,4, Anderson NN^5,6, Wagschal A^7,8, de Cabo R⁹, Horton JD^5,6, Lasunción MA^10,11, Näär AM^7,8, Suárez Y^1,2,3,4, Fernández-Hernando C^1,2,3,4. MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. Nat Med. 2015 Nov;21(11):1280-9.

https://www.ncbi.nlm.nih.gov/pubmed/26437365

5.Eberlé D¹, Hegarty B, Bossard P, Ferré P, Foufelle F. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie. 2004 Nov;86(11):839-48.

https://www.ncbi.nlm.nih.gov/pubmed/15589694

6.Harvard Medical School. News. MicoRNAs and Metabolism.

https://hms.harvard.edu/news/micrornas-and-metabolism

7. MGH – Four microRNAs identified as playing key roles in cholesterol, lipid metabolism

http://www.massgeneral.org/about/pressrelease.aspx?id=1862

LDL, HDL, TG, ApoA1 and ApoB: Genetic Loci Associated With Plasma Concentration of these Biomarkers – A Genome-Wide Analysis With Replication

Posted in Atherogenic Processes & Pathology, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Congenital Heart Disease, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Medical and Population Genetics, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Statistical Methods for Research Evaluation, tagged ApoA1, ApoB, Apolipoprotein A1, Cedars-Sinai Medical Center, HDL-cholesterol, High-density lipoprotein, LDL, Low-density lipoprotein, triglycerides on December 18, 2013| Leave a Comment »

LDL, HDL, TG, ApoA1 and ApoB: Genetic Loci Associated With Plasma Concentration of these Biomarkers – A Genome-Wide Analysis With Replication

Reporter: Aviva Lev-Ari, PhD, RN

Genetic Loci Associated With Plasma Concentration of Low-Density Lipoprotein Cholesterol, High-Density Lipoprotein Cholesterol, Triglycerides, Apolipoprotein A1, and Apolipoprotein B Among 6382 White Women in Genome-Wide Analysis With Replication

Daniel I. Chasman, PhD*, Guillaume Paré, MD, MS*, Robert Y.L. Zee, PhD, MPH, Alex N. Parker, PhD, Nancy R. Cook, ScD, Julie E. Buring, ScD, David J. Kwiatkowski, MD, PhD, Lynda M. Rose, MS, Joshua D. Smith, BS, Paul T. Williams, PhD, Mark J. Rieder, PhD, Jerome I. Rotter, MD, Deborah A. Nickerson, PhD, Ronald M. Krauss, MD,Joseph P. Miletich, MD and Paul M Ridker, MD, MPH

Author Affiliations

From the Center for Cardiovascular Disease Prevention (D.I.C., G.P., R.Y.L.Z., N.R.C., J.E.B., L.M.R., P.M.R.) and Donald W. Reynolds Center for Cardiovascular Research (D.I.C., G.P., R.Y.L.Z., N.R.C., D.J.K., P.M.R.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Amgen, Inc, Cambridge, Mass (A.N.P., J.M.P.); Department of Genome Sciences, University of Washington, Seattle, Wash (J.D.S., M.J.R., D.A.N.); Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, Calif (P.T.W., R.M.K.); Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, Calif (J.I.R.); and Children’s Hospital Oakland Research Institute, Oakland, Calif (R.M.K.).

Correspondence to Daniel I. Chasman, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02215. E-mail dchasman@rics.bwh.harvard.edu

Abstract

Background— Genome-wide genetic association analysis represents an opportunity for a comprehensive survey of the genes governing lipid metabolism, potentially revealing new insights or even therapeutic strategies for cardiovascular disease and related metabolic disorders.

Methods and Results— We have performed large-scale, genome-wide genetic analysis among 6382 white women with replication in 2 cohorts of 970 additional white men and women for associations between common single-nucleotide polymorphisms and low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein (Apo) A1, and ApoB. Genome-wide associations (P<5×10⁻⁸) were found at the PCSK9 gene, the APOB gene, the LPLgene, the APOA1-APOA5 locus, the LIPC gene, the CETP gene, the LDLR gene, and the APOE locus. In addition, genome-wide associations with triglycerides at the GCKRgene confirm and extend emerging links between glucose and lipid metabolism. Still other genome-wide associations at the 1p13.3 locus are consistent with emerging biological properties for a region of the genome, possibly related to the SORT1 gene. Below genome-wide significance, our study provides confirmatory evidence for associations at 5 novel loci with low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglycerides reported recently in separate genome-wide association studies. The total proportion of variance explained by common variation at the genome-wide candidate loci ranges from 4.3% for triglycerides to 12.6% for ApoB.

Conclusion— Genome-wide associations at the GCKR gene and near the SORT1gene, as well as confirmatory associations at 5 additional novel loci, suggest emerging biological pathways for lipid metabolism among white women.

SOURCE:

Circulation: Cardiovascular Genetics.2008; 1: 21-30

doi: 10.1161/ CIRCGENETICS.108.773168

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Serum carotenoid concentrations and metabolic syndrome: interaction with smoking

Posted in Biomarkers & Medical Diagnostics, Chemical Biology and its relations to Metabolic Disease, Metabolomics, Nutrigenomics, Nutrition, Population Health Management, Nutrition and Phytochemistry, tagged Antioxidant, Cardiovascular disease, carotenoids, Diabetes, HDL-cholesterol, hyperglycemia, oxidative stress, Reactive oxygen species, smoking, vitamins on May 27, 2013| 3 Comments »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Antioxidant micronutrients, such as vitamins and carotenoids, exist in abundance in fruit and vegetables and have been known to contribute to the body’s defence against reactive oxygen species. Numerous epidemiological studies have demonstrated that a high dietary consumption of fruit and vegetables rich in carotenoids or with high serum carotenoid concentrations results in lower risks of certain cancers, diabetes and cardiovascular disease. These epidemiological studies have suggested that antioxidant carotenoids may have a protective effect against diabetes or cardiovascular disease. However, the consumption of carotenoids in pharmaceutical forms for the treatment or prevention of these chronic diseases cannot be recommended, because some large randomized controlled trials did not reveal any reduction in cardiovascular events or type 2 diabetes with b-carotene. High doses of carotenoids used in the supplementation studies could have a pro-oxidant effect. Therefore, it is favourable to intake carotenoids from foods through the combination of other nutrients such as vitamins, minerals or phytochemicals, not by supplements.

The metabolic syndrome is a clustering of metabolic abnormalities that increase the risk for diabetes and cardiovascular disease. Typically, it includes excess weight, hyperglycaemia, evaluated blood pressure, low concentration of HDL-cholesterol, and hypertriacylglycerolaemia. This syndrome is emerging as one of the major medical and public health problems in Japan, and persons with this syndrome have an increased risk of morbidity and mortality due to cardiovascular disease and diabetes. Recently, many studies have examined the associations of dietary patterns with the metabolic syndrome and shown that diets rich in fruit and vegetables have been inversely associated with the metabolic syndrome. These previous reports suggest that a high intake of fruit and vegetables may reduce the risk of the metabolic syndrome through the beneficial combination of antioxidants, fibre, minerals, and other phytochemicals. Some recent cross-sectional and case–control studies have shown the associations of serum antioxidant status with the metabolic syndrome. Ford et al. reported that low intake and/or low serum concentrations of vitamins and carotenoids were associated with the risk of the metabolic syndrome. Although very few data are available about the associations of antioxidant carotenoids with the metabolic syndrome, people who have the metabolic syndrome are more likely to have increased oxidative stress than people who do not have this syndrome.

In some recent studies, it has been reported that oxidative stress, which is an imbalance between pro-oxidants and antioxidants, occurs more frequently in metabolic syndrome subjects than in non-metabolic syndrome subjects. Oxidative stress may play a key role in the pathophysiology of diabetes and cardiovascular disease. On the other hand, smoking is a potent oxidative stress in man. This increment of oxidative stress induced by smoking may develop insulin resistance, and increased insulin resistance may result in the clustering of the metabolic abnormality. Therefore, antioxidants could have a beneficial effect on reducing the risk of these conditions in smokers. However, there is limited information about the interaction of serum antioxidant carotenoids and the metabolic syndrome with smoking habit. This study was aimed to investigate the interaction of serum carotenoid concentrations and the metabolic syndrome with smoking. The association of the concentrations of six serum carotenoids, i.e. lutein, lycopene, a-carotene, b-carotene, b-cryptoxanthin and zeaxanthin, with metabolic syndrome status stratified by smoking status was evaluated crosssectionally.

In this study, the associations of the serum carotenoids with the metabolic syndrome stratified by smoking habit were evaluated cross-sectionally. A total of 1073 subjects (357 male and 716 female) who had received health examinations in the town of Mikkabi, Shizuoka Prefecture, Japan, participated in the study. Inverse associations of serum carotenoids with the metabolic syndrome were more evident among current smokers than non-smokers. These results support that antioxidant carotenoids may have a protective effect against development of the metabolic syndrome, especially in current smokers who are exposed to a potent oxidative stress.

Source References:

http://www.ncbi.nlm.nih.gov/pubmed/18445303

http://www.ncbi.nlm.nih.gov/pubmed/19450371

http://www.ncbi.nlm.nih.gov/pubmed/21216053

http://www.ncbi.nlm.nih.gov/pubmed/19631019

http://www.ncbi.nlm.nih.gov/pubmed/12324189

http://www.ncbi.nlm.nih.gov/pubmed/18689373