Browsing by Subject "CHOLESTEROL LEVELS"

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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.
  • Gil-Salcedo, Andres; Dugravot, Aline; Fayosse, Aurore; Dumurgier, Julien; Bouillon, Kim; Schnitzler, Alexis; Kivimäki, Mika; Singh-Manoux, Archana; Sabia, Séverine (2020)
    Severine Sabia and colleagues investigate whether healthy behaviors at midlife are associated with reduced risk of frailty at older ages.
  • Remes, Tiina Maria; Suo-Palosaari, Maria Helena; Koskenkorva, Päivi K. T.; Sutela, Anna K.; Toiviainen-Salo, Sanna-Maria; Arikoski, Pekka M.; Arola, Mikko O.; Heikkilä, Vesa-Pekka; Kapanen, Mika; Lähteenmäki, Päivi Maria; Lönnqvist, Tuula R. I.; Niiniviita, Hannele; Pokka, Tytti M-L; Porra, Liisa; Riikonen, V. Pekka; Seppälä, Jan; Sirkiä, Kirsti H.; Vanhanen, Antti; Rantala, Heikki M. J.; Harila-Saari, Arja H.; Ojaniemi, Marja K. (2020)
    Background. Cranial radiotherapy may damage the cerebral vasculature. The aim of this study was to understand the prevalence and risk factors of cerebrovascular disease (CVD) and white matter hyperintensities (WMHs) in childhood brain tumors (CBT) survivors treated with radiotherapy. Methods. Seventy CBT survivors who received radiotherapy were enrolled in a cross-sectional study at a median 20 years after radiotherapy cessation. The prevalence of and risk factors for CVD were investigated using MRI, MRA, and laboratory testing. Tumors, their treatment, and stroke-related data were retrieved from patients' files. Results. Forty-four individuals (63%) had CVD at a median age of 27 years (range, 16-43 years). The prevalence rates at 20 years for CVD, small-vessel disease, and large-vessel disease were 52%, 38%, and 16%, respectively. Ischemic infarcts were diagnosed in 6 survivors, and cerebral hemorrhage in 2. Lacunar infarcts were present in 7, periventricular or deep WMHs in 34 (49%), and mineralizing microangiopathy in 21 (30%) survivors. Multiple pathologies were detected in 44% of the participants, and most lesions were located in a high-dose radiation area. Higher blood pressure was associated with CVD and a presence of WMHs. Higher cholesterol levels increased the risk of ischemic infarcts and WMHs, and lower levels of high-density lipoprotein and higher waist circumference increased the risk of lacunar infarcts. Conclusions. Treating CBTs with radiotherapy increases the risk of early CVD and WMHs in young adult survivors. These results suggest an urgent need for investigating CVD prevention in CBT patients.