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- Saliba-Gustafsson, P., et al.
(författare)
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Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed-forward loop between LXR and autophagy
- 2019
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 286:6, s. 660-675
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Tidskriftsartikel (refereegranskat)abstract
- Background Hyperlipidaemia is a major risk factor for cardiovascular disease, and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development. Objective We sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 on subclinical atherosclerosis and the mechanism by which it acts. Methods A pan-European cohort of high-risk individuals where carotid intima-media thickness has been assessed was adopted. Human primary monocyte-derived macrophages were prepared from whole blood from individuals recruited by perilipin-2 genotype or from buffy coats from the Karolinska University hospital blood central. Results The Pro251 variant of perilipin-2 is associated with decreased intima-media thickness at baseline and over 30 months of follow-up. Using human primary monocyte-derived macrophages from carriers of the beneficial Pro251 variant, we show that this variant increases autophagy activity, cholesterol efflux and a controlled inflammatory response. Through extensive mechanistic studies, we demonstrate that increase in autophagy activity is accompanied with an increase in liver-X-receptor (LXR) activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol. Conclusions For the first time, we show that perilipin-2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin-2 modulates levels of the LXR ligand 27OH-cholesterol and initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its beneficial effects on subclinical atherosclerosis.
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- Bonomi, A, et al.
(författare)
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Analysis of the genetic variants associated with circulating levels of sgp130. Results from the IMPROVE study
- 2020
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Ingår i: Genes and immunity. - : Springer Science and Business Media LLC. - 1476-5470 .- 1466-4879. ; 21:2, s. 100-108
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Tidskriftsartikel (refereegranskat)abstract
- The genes regulating circulating levels of soluble gp130 (sgp130), the antagonist of the inflammatory response in atherosclerosis driven by interleukin 6, are largely unknown. Aims of the present study were to identify genetic loci associated with circulating sgp130 and to explore the potential association between variants associated with sgp130 and markers of subclinical atherosclerosis. The study is based on IMPROVE (n = 3703), a cardiovascular multicentre study designed to investigate the determinants of carotid intima media thickness, a measure of subclinical atherosclerosis. Genomic DNA was genotyped by the CardioMetaboChip and ImmunoChip. About 360,842 SNPs were tested for association with log-transformed sgp130, using linear regression adjusted for age, gender, and population stratification using PLINK v1.07. A p value of 1 × 10−5 was chosen as threshold for significance value. In an exploratory analysis, SNPs associated with sgp130 were tested for association with c-IMT measures. We identified two SNPs significantly associated with sgp130 levels and 24 showing suggestive association with sgp130 levels. One SNP (rs17688225) on chromosome 14 was positively associated with sgp130 serum levels (β = 0.03 SE = 0.007, p = 4.77 × 10−5) and inversely associated with c-IMT (c-IMTmean–maxβ = −0.001 SE = 0.005, p = 0.0342). Our data indicate that multiple loci regulate sgp130 levels and suggest a possible common pathway between sgp130 and c-IMT measures.
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- Damdimopoulou, Pauliina, et al.
(författare)
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A single dose of enterolactone activates estrogen signaling and regulates expression of circadian clock genes in mice.
- 2011
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Ingår i: The Journal of nutrition. - : Elsevier BV. - 1541-6100 .- 0022-3166. ; 141:9, s. 1583-9
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Tidskriftsartikel (refereegranskat)abstract
- Enterolactone (EL) is an enterolignan produced by gut microbiota from dietary plant lignans. Epidemiological and experimental studies suggest that EL and plant lignans may reduce the risk of breast and prostate cancer as well as cardiovascular disease. These effects are thought to at least in part involve modulation of estrogen receptor activity. Surprisingly little is known about the in vivo estrogenicity of EL. In the present study, we investigated the target tissues of EL, the genes affected by EL treatment, and the response kinetics. Following a single dose of EL, luciferase was significantly induced in reproductive and nonreproductive tissues of male and female 3xERE-luciferase mice, indicating estrogen-like activity. Microarray analysis revealed that EL regulated the expression of only 1% of 17β-estradiol target genes in the uterus. The majority of these genes were traditional estrogen target genes, but also members of the circadian signaling pathway were affected. Kinetic analyses showed that EL undergoes rapid phase II metabolism and is efficiently excreted. In vivo imaging demonstrated that the estrogen response followed similar, fast kinetics. We conclude that EL activates estrogen signaling in both male and female mice and that the transient responses may be due to the fast metabolism of the compound. Lastly, EL may represent a link among diet, gut microbiota, and circadian signaling.
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- Nurmi, Elias, et al.
(författare)
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Agreement between self-reported and registered age at asthma diagnosis in Finland
- 2024
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Ingår i: BMC PULMONARY MEDICINE. - 1471-2466. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionIn epidemiological studies, the age at asthma onset is often defined by patients' self-reported age at diagnosis. The reliability of this report might be questioned. Our objective was to evaluate the agreement between self-reported and registered age at asthma diagnosis and assess features contributing to the agreement.MethodsAs part of the FinEsS respiratory survey in 2016, randomly selected population samples of 13,435 from Helsinki and 8000 from Western Finland were studied. Self-reported age at asthma diagnosis was compared to age at asthma diagnosis registered in the Finnish register on special reimbursement for asthma medication. The reimbursement right is based on lung function criteria according to GINA and Finnish guidelines. If the difference was less than 5 years, self-reported diagnosis was considered reliable. Features associated with the difference between self-reported and registered age at asthma diagnosis were evaluated.ResultsAltogether 197 subjects from Helsinki and 144 from Western Finland were included. Of these, 61.9% and 77.8%, respectively, reported age at diagnosis reliably. Median difference between self-reported and registered age at diagnoses was - 2.0 years (IQR - 9.0 to 0) in Helsinki and - 1.0 (IQR - 4.3 to 0) in Western Finland indicating earlier self-reported age at diagnosis. More reliable self-report was associated with non-allergic subjects and subjects who reported having asthma diagnosis more recently.ConclusionsAgreement between self-reported and registered age at asthma diagnosis was good especially with adult-onset asthma patients. Poor agreement in early-onset asthma could be related to delay in registration due to reimbursement criteria. Self-reported age at asthma diagnosis was compared with health register data.Agreement between self-report and register was good in adult-onset asthma.If the diagnosis was reported far in the past, agreement with register was poorer.
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- Virtanen, Jyrki K., et al.
(författare)
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Vitamin D supplementation and prevention of cardiovascular disease and cancer in the Finnish Vitamin D Trial : a randomized controlled trial
- 2022
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Ingår i: American Journal of Clinical Nutrition. - : Oxford University Press. - 0002-9165 .- 1938-3207. ; 115:5, s. 1300-1310
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Vitamin D insufficiency is associated with risk of cardiovascular diseases (CVD) and cancer in observational studies, but evidence for benefits with vitamin D supplementation is limited.OBJECTIVES: To investigate the effects of vitamin D3 supplementation on CVD and cancer incidence.DESIGN: The study was a 5-year randomized placebo-controlled trial among 2495 male participants ≥ 60 years and post-menopausal female participants ≥ 65 years from a general Finnish population who were free of prior CVD or cancer. The study had three arms: placebo, 1600 IU/day or 3200 IU/day vitamin D3. Follow-up was by annual study questionnaires and national registry data. A representative sub-cohort of 551 participants had more detailed in-person investigations. The primary endpoints were incident major CVD and invasive cancer. Secondary endpoints included the individual components of the primary CVD endpoint (myocardial infarction, stroke, and CVD mortality), site-specific cancers and cancer death.RESULTS: During the follow-up, there were 41 (4.9%), 42 (5.0%) and 36 (4.3%) major CVD events in the placebo, 1600 IU/d (vs. placebo: hazard ratio (HR), 0.97;95% CI, 0.63,1.49; P = 0.89), and 3200 IU/d (HR, 0.84;95% CI, 0.54,1.31; P = 0.44) arms, respectively. Invasive cancer was diagnosed in 41 (4.9%), 48 (5.8%) and 40 (4.8%) participants in the placebo, 1600 IU/d (HR, 1.14;95% CI, 0.75,1.72; P = 0.55), and 3200 IU/d (HR, 0.95;95% CI, 0.61,1.47; P = 0.81) arms, respectively. There were no significant differences in the secondary endpoints or total mortality. In the sub-cohort, the mean (standard deviation) baseline serum 25-hydroxyvitamin D concentration was 75 (18) nmol/L. After 12 months, the concentrations were 73 (18) nmol/L, 100 (21) nmol/L and 120 (22) nmol/L in the placebo, 1600 IU/d and 3200 IU/d arms, respectively.CONCLUSIONS: Vitamin D3 supplementation did not lower the incidence of major CVD events or invasive cancer among older adults, possibly due to sufficient vitamin D status in most participants at baseline. Clinical Trial Registry number: ClinicalTrials.gov: NCT01463813, https://clinicaltrials.gov/ct2/show/NCT01463813.
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