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  • Hirvensalo, Päivi; Tornio, Aleksi; Neuvonen, Mikko; Tapaninen, Tuija; Paile-Hyvärinen, Maria; Kärjä, Vesa; Männistö, Ville T.; Pihlajamäki, Jussi; Backman, Janne T.; Niemi, Mikko (2018)
    To identify the genetic basis of interindividual variability in montelukast exposure, we determined its pharmacokinetics and sequenced 379 pharmacokinetic genes in 191 healthy volunteers. An intronic single nucleotide variation (SNV), strongly linked with UGT1A3*2, associated with reduced area under the plasma concentration-time curve (AUC(0-)) of montelukast (by 18% per copy of the minor allele; P=1.83 x 10(-10)). UGT1A3*2 was associated with increased AUC(0-) of montelukast acyl-glucuronide M1 and decreased AUC(0-) of hydroxymetabolites M5R, M5S, and M6 (P <10(-9)). Furthermore, SNVs in SLCO1B1 and ABCC9 were associated with the AUC(0-) of M1 and M5R, respectively. In addition, a candidate gene analysis suggested that CYP2C8 and ABCC9 SNVs also affect the AUC(0-) of montelukast. The found UGT1A3 and ABCC9 variants associated with increased expression of the respective genes in human liver samples. Montelukast and its hydroxymetabolites were glucuronidated by UGT1A3 in vitro. These results indicate that UGT1A3 plays an important role in montelukast pharmacokinetics, especially in UGT1A3*2 carriers.
  • Pirhonen, Juho; Arola, Johanna; Sädevirta, Sanja; Luukkonen, Panu; Karppinen, Sanna-Maria; Pihlajaniemi, Taina; Isomäki, Antti; Hukkanen, Mika; Yki-Jarvinen, Hannele; Ikonen, Elina (2016)
    Background and Aims Early detection of fibrosis is important in identifying individuals at risk for advanced liver disease in non-alcoholic fatty liver disease (NAFLD). We tested whether second-harmonic generation (SHG) and coherent anti-Stokes Raman scattering (CARS) microscopy, detecting fibrillar collagen and fat in a label-free manner, might allow automated and sensitive quantification of early fibrosis in NAFLD. Methods We analyzed 32 surgical biopsies from patients covering histological fibrosis stages 0-4, using multimodal label-free microscopy. Native samples were visualized by SHG and CARS imaging for detecting fibrillar collagen and fat. Furthermore, we developed a method for quantitative assessment of early fibrosis using automated analysis of SHG signals. Results We found that the SHG mean signal intensity correlated well with fibrosis stage and the mean CARS signal intensity with liver fat. Little overlap in SHG signal intensities between fibrosis stages 0 and 1 was observed. A specific fibrillar SHG signal was detected in the liver parenchyma outside portal areas in all samples histologically classified as having no fibrosis. This signal correlated with immunohistochemical location of fibrillar collagens I and III. Conclusions This study demonstrates that label-free SHG imaging detects fibrillar collagen deposition in NAFLD more sensitively than routine histological staging and enables observer-independent quantification of early fibrosis in NAFLD with continuous grading.
  • Luukkonen, Panu K.; Zhou, You; Haridas, Nidhina P. A.; Dwivedi, Om P.; Hyotylainen, Tuulia; Ali, Ashfaq; Juuti, Anne; Leivonen, Marja; Tukiainen, Taru; Ahonen, Linda; Scott, Emma; Palmer, Jeremy M.; Arola, Johanna; Orho-Melander, Marju; Vikman, Petter; Anstee, Quentin M.; Olkkonen, Vesa M.; Oresic, Matej; Groop, Leif; Yki-Jarvinen, Hannele (2017)
    Background: Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2(EK/KK)) have decreased expression of the TM6SF2 gene and increased risk of NAFLD and NASH. Unlike common 'obese/metabolic' NAFLD, these subjects lack hypertriglyceridemia and have lower risk of cardiovascular disease. In animals, phosphatidylcholine (PC) deficiency results in a similar phenotype. PCs surround the core of VLDL consisting of triglycerides (TGs) and cholesteryl-esters (CEs). We determined the effect of the TM6SF2 E167K on these lipids in the human liver and serum and on hepatic gene expression and studied the effect of TM6SF2 knockdown on hepatocyte handling of these lipids. Methods: Liver biopsies were taken from subjects characterized with respect to the TM6SF2 genotype, serum and liver lipidome, gene expression and histology. In vitro, after TM6SF2 knockdown in HuH-7 cells, we compared incorporation of different fatty acids into TGs, CEs, and PCs. Results: The TM6SF2(EK/KK) and TM6SF2EE groups had similar age, gender, BMI and HOMA-IR. Liver TGs and CEs were higher and liver PCs lower in the TM6SF2(EK/KK) than the TM6SF2EE group (p Conclusions: Hepatic lipid synthesis from PUFAs is impaired and could contribute to deficiency in PCs and increased intrahepatic TG in TM6SF2 E167K variant carriers. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
  • Adiels, Martin; Mardinoglu, Adil; Taskinen, Marja-Riitta; Boren, Jan (2015)
    To develop novel strategies for prevention and treatment of dyslipidemia, it is essential to understand the pathophysiology of dyslipoproteinemia in humans. Lipoprotein metabolism is a complex system in which abnormal concentrations of various lipoprotein particles can result from alterations in their rates of production, conversion, and/or catabolism. Traditional methods that measure plasma lipoprotein concentrations only provide static estimates of lipoprotein metabolism and hence limited mechanistic information. By contrast, the use of tracers labeled with stable isotopes and mathematical modeling, provides us with a powerful tool for probing lipid and lipoprotein kinetics in vivo and furthering our understanding of the pathogenesis of dyslipoproteinemia.
  • Sliz, Eeva; Sebert, Sylvain; Würtz, Peter; Kangas, Antti J.; Soininen, Pasi; Lehtimäki, Terho; Kähönen, Mika; Viikari, Jorma; Männikkö, Minna; Ala-Korpela, Mika; Raitakari, Olli T.; Kettunen, Johannes (2018)
    Fatty liver has been associated with unfavourable metabolic changes in circulation. To provide insights in fatty liver-related metabolic deviations, we compared metabolic association profile of fatty liver versus metabolic association profiles of genotypes increasing the risk of non-alcoholic fatty liver disease (NAFLD). The cross-sectional associations of ultrasound-ascertained fatty liver with 123 metabolic measures were determined in 1810 (N-fatty liver = 338) individuals aged 34-49 years from The Cardiovascular Risk in Young Finns Study. The association profiles of NAFLD-risk alleles in PNPLA3, TM6SF2, GCKR, and LYPLAL1 with the corresponding metabolic measures were obtained from a publicly available metabolomics GWAS including up to 24 925 Europeans. The risk alleles showed different metabolic effects: PNPLA3 rs738409-G, the strongest genetic NAFLD risk factor, did not associate with metabolic changes. Metabolic effects of GCKR rs1260326-T were comparable in many respects to the fatty liver associations. Metabolic effects of LYPLAL1 rs12137855-C were similar, but statistically less robust, to the effects of GCKR rs1260326-T. TM6SF2 rs58542926-T displayed opposite metabolic effects when compared with the fatty liver associations. The metabolic effects of the risk alleles highlight heterogeneity of the molecular pathways leading to fatty liver and suggest that the fatty liver-related changes in the circulating lipids and metabolites may vary depending on the underlying pathophysiological mechanism. Despite the robust cross-sectional associations on population level, the present results showing neutral or cardioprotective metabolic effects for some of the NAFLD risk alleles advocate that hepatic lipid accumulation by itself may not increase the level of circulating lipids or other metabolites.
  • Setti, Mounir Ould; Voutilainen, Ari; Tajik, Behnam; Niskanen, Leo; Tuomainen, Tomi-Pekka (2021)
    Background and objectives Fatty liver disease (FLD) and hypertension are separately associated with cardiovascular (CV) mortality. The two conditions are related in multiple ways. This work aimed to study the joint effect and interaction of FLD and hypertension in respect to overall and CV mortality. Methods The population-based cohort, Kuopio Ischaemic Disease Risk Factor Study, followed 1569 middle-aged non-diabetic Finnish men for 34 years. Considering adjustment for age, body mass index, smoking and alcohol consumption, separate and combined effects of FLD and hypertension and their interaction at the multiplicative and additive scales regarding all-cause and CV death were assessed using Cox proportional hazards models. Results FLD and hypertension coexisted in 8.54% of the men (n = 134). FLD and hypertension associated, independently and combined, with an increased hazard of all-cause and CV deaths. Non-CV mortality associated with FLD, but not with hypertension. We found a negative interaction between FLD and hypertension regarding the hazard of all-cause (relative excess risk due to interaction (RERI), -0.97; 95% confidence interval (CI), -1.65 to -0.28) and CV mortality (RERI, -1.74; 95% CI, -2.98 to -0.5). The interaction was also found on a multiplicative scale. Conclusions We found evidence of a negative interaction between FLD and hypertension in respect to CV mortality. We thus recommend adjusting for FLD or hypertension when studying the effect of the other condition on mortality or CV diseases in middle-aged men.
  • Tauriainen, Milla-Maria; Mannisto, Ville; Kaminska, Dorota; Vaittinen, Maija; Karja, Vesa; Kakela, Pirjo; Venesmaa, Sari; Gylling, Helena; Pihlajamaki, Jussi (2018)
    Background and aims: Non-alcoholic fatty liver disease (NAFLD) associates with low levels of serum plant sterols in cross-sectional studies. In addition, it has been suggested that the hepatic sterol transport mechanisms are altered in NAFLD. Therefore, we investigated the association between serum, liver and bile plant sterols and sitostanol with NAFLD. Methods: Out of the 138 individuals (age: 46.3 +/- 8.9, body mass index: 43.3 +/- 6.9 kg/m(2), 28% men and 72% women), 44 could be histologically categorized to have normal liver, and 94 to have NAFLD. Within the NAFLD group, 28 had simple steatosis and 27 had non-alcoholic steatohepatitis. Plant sterols and sitostanol were measured from serum (n = 138), liver (n = 38), and bile (n = 41). The mRNA expression of genes regulating liver sterol metabolism and inflammation was measured (n = 102). Results: Liver and bile sitostanol ratios to cholesterol were higher in those with NAFLD compared to those with histologically normal liver (all P <0.022). Furthermore, liver sitostanol to cholesterol ratio correlated positively with histological steatosis and lobular inflammation (r(s) > 0.407, P <0.01 for both). In contrast, liver sitosterol to cholesterol ratio correlated negatively with steatosis (r(s) = -0.392, P = 0.015) and lobular inflammation (r(s) = -0.395, P = 0.014). Transcriptomics analysis revealed suggestive correlations between serum plant sterol levels and mRNA expression. Conclusion: Our study showed that liver and bile sitostanol ratios to cholesterol associated positively and liver sitosterol ratio to cholesterol associated negatively with liver steatosis and inflammation in obese individuals with NAFLD..