Browsing by Subject "hypercholesterolemia"

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  • Karpale, M; Karajamaki, AJ; Kummu, O; Gylling, H; Hyotylainen, T; Oresic, M; Tolonen, A; Hautajarvi, H; Savolainen, MJ; Ala-Korpela, M; Hukkanen, J; Hakkola, J (2021)
    Background and Purpose Many drugs and environmental contaminants induce hypercholesterolemia and promote the risk of atherosclerotic cardiovascular disease. We tested the hypothesis that pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, regulates the level of circulating atherogenic lipids in humans and utilized mouse experiments to identify the mechanisms involved. Experimental Approach We performed serum NMR metabolomics in healthy volunteers administered rifampicin, a prototypical human PXR ligand or placebo in a crossover setting. We used high-fat diet fed wild-type and PXR knockout mice to investigate the mechanisms mediating the PXR-induced alterations in cholesterol homeostasis. Key Results Activation of PXR induced cholesterogenesis both in pre-clinical and clinical settings. In human volunteers, rifampicin increased intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and total cholesterol and lathosterol-cholesterol ratio, a marker of cholesterol synthesis, suggesting increased cholesterol synthesis. Experiments in mice indicated that PXR activation causes widespread induction of the cholesterol synthesis genes including the rate-limiting Hmgcr and upregulates the intermediates in the Kandutsch-Russell cholesterol synthesis pathway in the liver. Additionally, PXR activation induced plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a negative regulator of hepatic LDL uptake, in both mice and humans. We propose that these effects were mediated through increased proteolytic activation of sterol regulatory element-binding protein 2 (SREBP2) in response to PXR activation. Conclusion and Implications PXR activation induces cholesterol synthesis, elevating LDL and total cholesterol in humans. The PXR-SREBP2 pathway is a novel regulator of the cholesterol and PCSK9 synthesis and a molecular mechanism for drug- and chemical-induced hypercholesterolemia.
  • Ramo, Joel T.; Ripatti, Pietari; Tabassum, Rubina; Soderlund, Sanni; Matikainen, Niina; Gerl, Mathias J.; Klose, Christian; Surma, Michal A.; Stitziel, Nathan O.; Havulinna, Aki S.; Pirinen, Matti; Salomaa, Veikko; Freimer, Nelson B.; Jauhiainen, Matti; Palotie, Aarno; Taskinen, Marja-Riitta; Simons, Kai; Ripatti, Samuli (2019)
    Background-We asked whether, after excluding familial hypercholesterolemia, individuals with high low-density lipoprotein cholesterol (LDL-C) or triacylglyceride levels and a family history of the same hyperlipidemia have greater coronary artery disease risk or different lipidomic profiles compared with population-based hyperlipidemias. Methods and Results-We determined incident coronary artery disease risk for 755 members of 66 hyperlipidemic families (>2 first-degree relatives with similar hyperlipidemia) and 19 644 Finnish FINRISK population study participants. We quantified 151 circulating lipid species from 550 members of 73 hyperlipidemic families and 897 FINRISK participants using mass spectrometric shotgun lipidomics. Familial hypercholesterolemia was excluded using functional LDL receptor testing and genotyping. Hyperlipidemias (LDL-C or triacylglycerides >90th population percentile) associated with increased coronary artery disease risk in meta-analysis of the hyperlipidemic families and the population cohort (high LDL-C: hazard ratio, 1.74 [95% CI, 1.48-2.04]; high triacylglycerides: hazard ratio, 1.38 [95% CI 1.09-1.74]). Risk estimates were similar in the family and population cohorts also after adjusting for lipid-lowering medication. In lipidomic profiling, high LDL-C associated with 108 lipid species, and high triacylglycerides associated with 131 lipid species in either cohort (at 5% false discovery rate; P-value range 0.038-2.3x 10(-56)). Lipidomic profiles were highly similar for hyperlipidemic individuals in the families and the population (LDL-C: r=0.80; triacylglycerides: r=0.96; no lipid species deviated between the cohorts). Conclusions-Hyperlipidemias with family history conferred similar coronary artery disease risk as population-based hyperlipidemias. We identified distinct lipidomic profiles associated with high LDL-C and triacylglycerides. Lipidomic profiles were similar between hyperlipidemias with family history and population-ascertained hyperlipidemias, providing evidence of similar and overlapping underlying mechanisms.
  • Vuorio, Alpo; Kovanen, Petri T. (2018)
    This review covers the current knowledge about plant stanol esters as a dietary treatment option for heterozygous familial hypercholesterolemia (he-FH) children. The current estimation of the prevalence of he-FH is about one out of 200-250 persons. In this autosomal dominant disease, the concentration of plasma low-density lipoprotein cholesterol (LDL-C) is strongly elevated since birth. Quantitative coronary angiography among he-FH patients has revealed that stenosing atherosclerotic plaques start to develop in he-FH males in their twenties and in he-FH females in their thirties, and that the magnitude of the plaque burden predicts future coronary events. The cumulative exposure of coronary arteries to the lifelong LDL-C elevation can be estimated by calculating the LDL-C burden (LDL-C level x years), and it can also be used to demonstrate the usefulness of dietary stanol ester treatment. Thus, when compared with untreated he-FH patients, the LDL-C burden of using statin from the age of 10 is 15% less, and if he-FH patients starts to use dietary stanol from six years onwards and a combination of statin and dietary stanol from 10 years onwards, the LDL-C burden is 21% less compared to non-treated he-FH patients. We consider dietary stanol treatment of he-FH children as a part of the LDL-C-lowering treatment package as safe and cost-effective, and particularly applicable for the family-centered care of the entire he-FH families.
  • FinnGen Project; Ripatti, Pietari; Rämö, Joel T.; Mars, Nina J.; Fu, Yu; Lin, Jake; Söderlund, Sanni; Benner, Christian; Surakka, Ida; Kiiskinen, Tuomo; Havulinna, Aki S.; Palta, Priit; Freimer, Nelson B.; Widén, Elisabeth; Salomaa, Veikko; Tukiainen, Taru; Pirinen, Matti; Palotie, Aarno; Taskinen, Marja-Riitta; Ripatti, Samuli (2020)
    Background: Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). While monogenic familial hypercholesterolemia associates with severely increased CAD risk, it remains less clear to what extent a high polygenic load of a large number of LDL (low-density lipoprotein) cholesterol (LDL-C) or triglyceride (TG)-increasing variants associates with increased CAD risk. Methods: We derived polygenic risk scores (PRSs) with approximate to 6M variants separately for LDL-C and TG with weights from a UK Biobank-based genome-wide association study with approximate to 324K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the National FINRISK Study (FINRISK) cohort and to CAD risk in 135 638 individuals (13 753 CAD cases) from the FinnGen project (FinnGen). Results: In FINRISK, median LDL-C was 3.39 (95% CI, 3.38-3.40) mmol/L, and it ranged from 2.87 (95% CI, 2.82-2.94) to 3.78 (95% CI, 3.71-3.83) mmol/L between the lowest and highest 5% of the LDL-C PRS distribution. Median TG was 1.19 (95% CI, 1.18-1.20) mmol/L, ranging from 0.97 (95% CI, 0.94-1.00) to 1.55 (95% CI, 1.48-1.61) mmol/L with the TG PRS. In FinnGen, comparing the highest 5% of the PRS to the lowest 95%, CAD odds ratio was 1.36 (95% CI, 1.24-1.49) for the LDL-C PRS and 1.31 (95% CI, 1.19-1.43) for the TG PRS. These estimates were only slightly attenuated when adjusting for a CAD PRS (odds ratio, 1.26 [95% CI, 1.16-1.38] for LDL-C and 1.24 [95% CI, 1.13-1.36] for TG PRS). Conclusions: The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and partially overlapping with a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing additional guidance for clinical translation.
  • Herttua, Kimmo; Martikainen, Pekka; Batty, G. David; Kivimäki, Mika (2016)
    BACKGROUND Poor adherence to medication regimens is common, potentially contributing to the occurrence of related disease. OBJECTIVES The authors sought to assess the risk of fatal stroke associated with nonadherence to statin and/ or antihypertensive therapy. METHODS We conducted a population-based study using electronic medical and prescription records from Finnish national registers in 1995 to 2007. Of the 58,266 hypercholesterolemia patients age 30+ years without pre-existing stroke or cardiovascular disease, 532 patients died of stroke (cases), and 57,734 remained free of incident stroke (controls) during the mean follow-up of 5.5 years. We captured year-by-year adherence to statin and antihypertensive therapy in both study groups and estimated the excess risk of stroke death associated with nonadherence. RESULTS In all hypercholesterolemia patients, the adjusted odds ratio for stroke death for nonadherent compared with adherent statin users was 1.35 (95% confidence interval [CI] 1.04 to 1.74) 4 years before and 2.04 (95% CI: 1.72 to 2.43) at the year of stroke death or the end of the follow-up. In hypercholesterolemia patients with hypertension, relative to those who adhered to statins and antihypertensive therapy, the odds ratio at the year of stroke death was 7.43 (95% CI: 5.22 to 10.59) for those nonadherent both to statin and antihypertensive therapy, 1.82 (95% CI: 1.43 to 2.33) for those non-adherent to statin but adherent to antihypertensive therapy, and 1.30 (95% CI: 0.53 to 3.20) for those adherent to statin, but nonadherent to antihypertensive, therapy. CONCLUSIONS Individuals with hypercholesterolemia and hypertension who fail to take their prescribed statin and antihypertensive medication experience a substantially increased risk of fatal stroke. The risk is lower if the patient is adherent to either one of these therapies. (C) 2016 by the American College of Cardiology Foundation.