Multiple microRNA regulation of lipoprotein lipase gene abolished by 3′UTR polymorphisms in a triglyceride-lowering haplotype harboring p.Ser474Ter

Caussy, Cyrielle; Charrière, Sybil; Meirhaeghe, Aline; Dallongeville, Jean; Lefai, Étienne; Rome, Sophie; Cuerq, Charlotte; Euthine, Vanessa; Delay, Mireille; Marmontel, Oriane; Filippo, Mathilde Di; Lagarde, Michel; Moulin, Philippe; Marçais, Christophe

doi:10.1016/j.atherosclerosis.2016.01.010

Cited by 23 publications

(11 citation statements)

References 35 publications

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“…p.Ser447Ter) variant that lowers TG levels (6). Interestingly, variants disrupting microRNA binding sites in the 3 ′ -untranslated region of LPL are reported to be in linkage disequilibrium with p.Ser474Ter, which may suggest that the disruption in gene regulation may also contribute to the GOF mechanism (7,8).…”

Section: Functional Impact Of Genetic Variantsmentioning

confidence: 99%

Genetics of Hypertriglyceridemia

2020

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Hypertriglyceridemia, a commonly encountered phenotype in cardiovascular and metabolic clinics, is surprisingly complex. A range of genetic variants, from single-nucleotide variants to large-scale copy number variants, can lead to either the severe or mild-to-moderate forms of the disease. At the genetic level, severely elevated triglyceride levels resulting from familial chylomicronemia syndrome (FCS) are caused by homozygous or biallelic loss-of-function variants in LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes. In contrast, susceptibility to multifactorial chylomicronemia (MCM), which has an estimated prevalence of ∼1 in 600 and is at least 50-100-times more common than FCS, results from two different types of genetic variants: (1) rare heterozygous variants (minor allele frequency <1%) with variable penetrance in the five causal genes for FCS; and (2) common variants (minor allele frequency >5%) whose individually small phenotypic effects are quantified using a polygenic score. There is indirect evidence of similar complex genetic predisposition in other clinical phenotypes that have a component of hypertriglyceridemia, such as combined hyperlipidemia and dysbetalipoproteinemia. Future considerations include: (1) evaluation of whether the specific type of genetic predisposition to hypertriglyceridemia affects medical decisions or long-term outcomes; and (2) searching for other genetic contributors, including the role of genome-wide polygenic scores, novel genes, non-linear gene-gene or geneenvironment interactions, and non-genomic mechanisms including epigenetics and mitochondrial DNA.

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Section: Functional Impact Of Genetic Variantsmentioning

confidence: 99%

Genetics of Hypertriglyceridemia

2020

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“…FFAs which are result of LPL activity are then oxidized by a variety of cell types, such as skeletal and myocardial myocytes, or are resynthetized together with glycerol in TGs and in this form stored in adipose tissue. 18) On the other hand, the chylomicron remnants, which are rich in cholesterol esters and Apo E, are removed from circulation by binding to the LDL receptors or the LDL receptor-related proteins on the liver cells. LMF1 is a gene product that regulates TGs metabolism influencing LPL and hepatic lipase (HL).…”

Section: Metabolism Of Triglyceride-rich Lipoproteinsmentioning

confidence: 99%

Triglyceride-Rich Lipoproteins and Novel Targets for Anti-atherosclerotic Therapy

Reiner

2018

Korean Circ J

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Although elevated serum low-density lipoprotein-cholesterol (LDL-C) is without any doubts accepted as an important risk factor for cardiovascular disease (CVD), the role of elevated triglycerides (TGs)-rich lipoproteins as an independent risk factor has until recently been quite controversial. Recent data strongly suggest that elevated TG-rich lipoproteins are an independent risk factor for CVD and that therapeutic targeting of them could possibly provide further benefit in reducing CVD morbidity, events and mortality, apart from LDL-C lowering. Today elevated TGs are treated with lifestyle interventions, and with fibrates which could be combined with omega-3 fatty acids. There are also some new drugs. Volanesorsen, is an antisense oligonucleotid that inhibits the production of the Apo C-III which is crucial in regulating TGs metabolism because it inhibits lipoprotein lipase (LPL) and hepatic lipase activity but also hepatic uptake of TGs-rich particles. Evinacumab is a monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3) and it seems that it can substantially lower elevated TGs levels because ANGPTL3 also regulates TGs metabolism. Pemafibrate is a selective peroxisome proliferator-activated receptor alpha modulator which also decreases TGs, and improves other lipid parameters. It seems that it also has some other possible antiatherogenic effects. Alipogene tiparvovec is a nonreplicating adeno-associated viral vector that delivers copies of the LPL gene to muscle tissue which accelerates the clearance of TG-rich lipoproteins thus decreasing extremely high TGs levels. Pradigastat is a novel diacylglycerol acyltransferase 1 inhibitor which substantially reduces extremely high TGs levels and appears to be promising in treatment of the rare familial chylomicronemia syndrome.

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“…The hsa-miR-1277-3p and bta-miR-1277-R-1 sequences are identical. In humans, has-miR-1277-3p downregulates lipoprotein lipase, which hydrolyzes lipoprotein triacylglycerides (Caussy et al, 2016). Placental insufficiencyinduced IUGR has been linked to the accumulation of adipose tissue and insulin resistance in postnatal life (Garofano et al, 1997;Béringue et al, 2002).…”

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confidence: 99%

Ergot alkaloid exposure during gestation alters: 3. Fetal growth, muscle fiber development, and miRNA transcriptome1

Greene

Britt

Powell

et al. 2019

Journal of Animal Science

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The objective of this study was to assess how exposure to ergot alkaloids during 2 stages of gestation alters fetal growth, muscle fiber formation, and miRNA expression. Pregnant ewes (n = 36; BW = 83.26 ± 8.14 kg; 4/group; 9 groups) were used in a 2 × 2 factorial arrangement with 2 tall fescue seed treatments [endophyte-infected (E+) vs. endophyte-free (E−)] fed during 2 stages of gestation (MID, days 35 to 85 vs. LATE, days 86 to 133), which created 4 possible treatments (E−/E−, E+/E−, E−/E+, or E+/E+). Ewes were individually fed a total mixed ration containing E+ or E− fescue seed according to treatment assignment. Terminal surgeries were conducted on day 133 of gestation for the collection of fetal measurements and muscle samples. Data were analyzed as a 2 × 2 factorial with fescue treatment, stage of gestation, and 2-way interaction as fixed effects. Fetuses exposed to E+ seed during LATE gestation had reduced (P = 0.0020) fetal BW by 10% compared with E− fetuses; however, fetal body weight did not differ (P = 0.41) with E+ exposure during MID gestation. Fetuses from ewes fed E+ seed during MID and LATE gestation tended to have smaller (P = 0.058) kidney weights compared with E− fetuses. Liver weight was larger (P = 0.0069) in fetuses fed E− during LATE gestation compared with E+. Fetal brain weight did not differ by fescue treatment fed during MID (P = 0.36) or LATE (P = 0.40) gestation. The percentage of brain to empty body weight (EBW) was greater (P = 0.0048) in fetuses from ewes fed E+ fescue seed during LATE gestation, which is indicative of intrauterine growth restriction (IUGR). Primary muscle fiber number was lower (P = 0.0005) in semitendinosus (STN) of fetuses exposed to E+ during MID and/or LATE gestation compared with E−/E−. miRNA sequencing showed differential expression (P < 0.010) of 6 novel miRNAs including bta-miR-652_R+1, mdo-miR-22-3p, bta-miR-1277_R-1, ppy-miR-133a_L+1_1ss5TG, hsa-miR-129-1-3p, and ssc-miR-615 in fetal STN muscle. These miRNA are associated with glucose transport, insulin signaling, intracellular ATP, hypertension, or adipogenesis. This work supports the hypothesis that E+ tall fescue seed fed during late gestation reduces fetal weight and causes asymmetrical growth, which is indicative of IUGR. Changes in primary fiber number and miRNA of STN indicate that exposure to E+ fescue fed during MID and LATE gestation alters fetal muscle development that may affect postnatal muscle growth and meat quality.

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Multiple microRNA regulation of lipoprotein lipase gene abolished by 3′UTR polymorphisms in a triglyceride-lowering haplotype harboring p.Ser474Ter

Cited by 23 publications

References 35 publications

Genetics of Hypertriglyceridemia

Genetics of Hypertriglyceridemia

Triglyceride-Rich Lipoproteins and Novel Targets for Anti-atherosclerotic Therapy

Ergot alkaloid exposure during gestation alters: 3. Fetal growth, muscle fiber development, and miRNA transcriptome1

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