Papers by Jussi Pihlajamäki
Cell Metabolism, 2011
Alternative mRNA splicing provides transcript diversity and may contribute to human disease. We d... more Alternative mRNA splicing provides transcript diversity and may contribute to human disease. We demonstrate that expression of several genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. We evaluated a representative splicing factor, SFRS10, down-regulated in both obese human liver and muscle and in high fat-fed mice, and determined metabolic impact of reduced expression. SFRS10-specific siRNA induces lipogenesis and lipid accumulation in hepatocytes. Moreover, Sfrs10 heterozygous mice have increased hepatic lipogenic gene expression, VLDL secretion, and plasma triglycerides. We demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10; reduced SFRS10 favors the lipogenic β isoform of LPIN1. Importantly, LPIN1β-specific siRNA abolished lipogenic effects of decreased SFRS10 expression. Together, our results indicate that reduced expression of
Nutrients
Eating competence (EC) is characterized by positive attitudes towards food and eating, having reg... more Eating competence (EC) is characterized by positive attitudes towards food and eating, having regular meals, eating a variety of foods, and internally regulated eating. We investigated the associations of changes in EC with changes in lifestyle, anthropometrics and biomarkers of glucose and lipid metabolism in 2291 adults at increased risk of type 2 diabetes as part of the StopDia study conducted in primary healthcare. EC and diet quality were assessed with validated digital questionnaires. During the intervention, the participants received either (1) the digital lifestyle intervention, (2) the combined digital and face-to-face group-based lifestyle intervention, or (3) standard care. EC increased among the participants independent of the intervention type. Increase in EC was associated with an increase in diet quality, high-density lipoprotein (HDL) cholesterol, and with a decrease in body mass index and waist circumference, regardless of baseline EC. Of the subdomains of EC, the c...
International Journal of Environmental Research and Public Health
Lack of tools to evaluate the quality of diet impedes dietary counselling in healthcare. We const... more Lack of tools to evaluate the quality of diet impedes dietary counselling in healthcare. We constructed a scoring for a validated food intake questionnaire, to measure the adherence to a healthy diet that prevents type 2 diabetes (T2D). The Healthy Diet Index (HDI) consists of seven weighted domains (meal pattern, grains, fruit and vegetables, fats, fish and meat, dairy, snacks and treats). We studied the correlations of the HDI with nutrient intakes calculated from 7-day food records among 52 men and 25 women, and associations of HDI with biomarkers and anthropometrics among 645 men and 2455 women. The HDI correlated inversely with total fat (Pearson’s r = −0.37), saturated fat (r = −0.37), monounsaturated fat (r = −0.37), and the glycaemic index of diet (r = −0.32) and positively with carbohydrates (r = 0.23), protein (r = 0.25), fibre (r = 0.66), magnesium (r = 0.26), iron (r = 0.25), and vitamin D (r = 0.27), (p < 0.05 for all). In the linear regression model adjusted for BMI...
Nutrients
Redesigning choice environments appears a promising approach to encourage healthier eating and ph... more Redesigning choice environments appears a promising approach to encourage healthier eating and physical activity, but little evidence exists of the feasibility of this approach in real-world settings. The aim of this paper is to portray the implementation and feasibility assessment of a 12-month mixed-methods intervention study, StopDia at Work, targeting the environment of 53 diverse worksites. The intervention was conducted within a type 2 diabetes prevention study, StopDia. We assessed feasibility through the fidelity, facilitators and barriers, and maintenance of implementation, building on implementer interviews (n = 61 informants) and observations of the worksites at six (t1) and twelve months (t2). We analysed quantitative data with Kruskall–Wallis and Mann–Whitney U tests and qualitative data with content analysis. Intervention sites altogether implemented 23 various choice architectural strategies (median 3, range 0–14 strategies/site), employing 21 behaviour change mechani...
Nutrients
Background and Aims: Gut microbiota-derived metabolites play a vital role in maintenance of human... more Background and Aims: Gut microbiota-derived metabolites play a vital role in maintenance of human health and progression of disorders, including obesity and type 2 diabetes (T2D). Indole-3-propionic acid (IPA), a gut-derived tryptophan metabolite, has been recently shown to be lower in individuals with obesity and T2D. IPA’s beneficial effect on liver health has been also explored in rodent and cell models. In this study, we investigated the association of IPA with human liver histology and transcriptomics, and the potential of IPA to reduce hepatic stellate cell activation in vitro. Methods: A total of 233 subjects (72% women; age 48.3 ± 9.3 years; BMI 43.1 ± 5.4 kg/m2) undergoing bariatric surgery with detailed liver histology were included. Circulating IPA levels were measured using LC-MS and liver transcriptomics with total RNA-sequencing. LX-2 cells were used to study hepatoprotective effect of IPA in cells activated by TGF-β1. Results: Circulating IPA levels were found to be l...
Nutrients
A healthy dietary pattern is associated with a lower risk of metabolic syndrome (MetS) and reduce... more A healthy dietary pattern is associated with a lower risk of metabolic syndrome (MetS) and reduced inflammation. To explore this at the molecular level, we investigated the effect of a Nordic diet (ND) on changes in the gene expression profiles of inflammatory and lipid-related genes in peripheral blood mononuclear cells (PBMCs) of individuals with MetS. We hypothesized that the intake of an ND compared to a control diet (CD) would alter the expression of inflammatory genes and genes involved in lipid metabolism. The individuals with MetS underwent an 18/24-week randomized intervention to compare a ND with a CD. Eighty-eight participants (66% women) were included in this sub-study of the larger SYSDIET study. Fasting PBMCs were collected before and after the intervention and changes in gene expression levels were measured using TaqMan Array Micro Fluidic Cards. Forty-eight pre-determined inflammatory and lipid related gene transcripts were analyzed. The expression level of the gene ...
BMJ Open Gastroenterology
ObjectiveFatty liver disease (FLD) has been associated with extrahepatic morbidity outcomes. Howe... more ObjectiveFatty liver disease (FLD) has been associated with extrahepatic morbidity outcomes. However, reports on the association of FLD, assessed using fatty liver index (FLI), with mortality outcomes have been inconsistent. Our objective was to examine the effect of metabolic factors (blood pressure, insulin, fasting glucose, lipoproteins) on the associations of FLI with mortality outcomes among middle-aged men.Study designProspective cohort study.MethodsOur subjects were 1893 men at baseline from 1984 to 1989 in the Kuopio Ischaemic Heart Disease Risk Factor Study cohort. Multivariable Cox regression models were used to analyse the association of baseline FLI, with the HRs for all-cause, disease, cardiovascular, non-cardiovascular and cancer mortality outcomes.ResultsThe mean FLI in the FLI categories were 16.2 in the low and reference category (FLI<30), 43.4 in the intermediate FLI category (FLI=30–<60) and 77.5 in the high FLI (FLD) category (FLI≥60). Over an average follo...
Clinical Epigenetics
Following publication of the original article [1], the author reported the title of this article ... more Following publication of the original article [1], the author reported the title of this article has been misspelled. The correct title is "Liver DNA methylation of FADS2 associates with FADS2 genotype". It has been corrected in the original article as well. The publisher apologizes for any inconvenience caused by this error.
BMC Public Health
Background: The StopDia study is based on the convincing scientific evidence that type 2 diabetes... more Background: The StopDia study is based on the convincing scientific evidence that type 2 diabetes (T2D) and its comorbidities can be prevented by a healthy lifestyle. The need for additional research is based on the fact that the attempts to translate scientific evidence into actions in the real-world health care have not led to permanent and cost-effective models to prevent T2D. The specific aims of the StopDia study following the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework are to 1) improve the Reach of individuals at increased risk, 2) evaluate the Effectiveness and cost-effectiveness of the digital lifestyle intervention and the digital and face-to-face group lifestyle intervention in comparison to routine care in a randomized controlled trial (RCT), and 3) evaluate the Adoption and Implementation of the StopDia model by the participants and the health care organizations at society level. Finally, we will address the Maintenance of the lifestyle changes at participant level and that of the program at organisatory level after the RCT. Methods: The StopDia study is carried out in the primary health care system as part of the routine actions of three provinces in Finland, including Northern Savo, Southern Carelia, and Päijät-Häme. We estimate that one fifth of adults aged 18-70 years living in these areas are at increased risk of T2D. We recruit the participants using the StopDia Digital Screening Tool, including questions from the Finnish Diabetes Risk Score (FINDRISC). About 3000 individuals at increased risk of T2D (FINDRISC ≥12 or a history of gestational diabetes, impaired fasting glucose, or impaired glucose tolerance) participate in the one-year randomized controlled trial. We monitor lifestyle factors using the StopDia Digital Questionnaire and metabolism using laboratory tests performed as part of routine actions in the health care system.
Clinical Epigenetics
Background: Non-alcoholic fatty liver disease has been associated with increased mRNA expression ... more Background: Non-alcoholic fatty liver disease has been associated with increased mRNA expression of FADS2 in the liver and estimated activity of delta-6 desaturase in serum, encoded by the FADS2 gene. Since DNA methylation in the FADS1/2/3 gene cluster has been previously linked with genetic variants and desaturase activities, we now aimed to discover factors regulating DNA methylation of the CpG sites annotated to FADS1/2 genes. Methods: DNA methylation levels in the CpG sites annotated to FADS2 and FADS1 were analyzed from liver samples of 95 obese participants of the Kuopio Obesity Surgery Study (34 men and 61 women, age 49.5 ± 7.7 years, BMI 43.0 ± 5.7 kg/m 2) using the Infinium HumanMethylation450 BeadChip (Illumina). Associations between DNA methylation levels and estimated delta-6 and delta-5 desaturase enzyme activities, liver histology, hepatic mRNA expression, FADS1/2 genotypes, and erythrocyte folate levels were analyzed. Results: We found a negative correlation between DNA methylation levels of cg06781209 and cg07999042 and hepatic FADS2 mRNA expression (both p < 0.05), and with estimated delta-6 desaturase activity based on both liver and serum fatty acids (all p < 0.05). Interestingly, the methylation level of cg07999042 (p = 0.001) but not of cg06781209 (p = 0.874) was associated with FADS2 variant rs174616. Conclusions: Genetic variants of FADS2 may contribute to the pathogenesis of non-alcoholic fatty liver disease by modifying DNA methylation.
The American Journal of Clinical Nutrition
Background The health benefits of substituting dietary polyunsaturated fatty acids (PUFAs) for sa... more Background The health benefits of substituting dietary polyunsaturated fatty acids (PUFAs) for saturated fatty acids are well known. However, limited information exists on how the response to dietary intake of linoleic acid (LA; 18:2n–6) is modified by polymorphisms in the fatty acid desaturase (FADS) gene cluster. Objectives The aim of the current study was to test the hypothesis that the FADS1 rs174550 genotype modifies the effect of dietary LA intake on the fatty acid composition of plasma lipids, fasting glucose, and high-sensitivity C-reactive protein (hsCRP). Methods Associations were investigated between genotype, plasma PUFAs, fasting glucose, and hsCRP concentrations in the cross-sectional, population-based Metabolic Syndrome in Men cohort (n = 1337). In addition, 62 healthy men from the cohort who were homozygotes for the TT or CC genotype of the FADS1 rs174550 were recruited to a 4-wk intervention (FADSDIET) with an LA-enriched diet. The fatty acid composition of plasma P...
Basic & clinical pharmacology & toxicology, 2018
Several single nucleotide variations (SNVs) affect carboxylesterase 1 (CES1) activity, but the ef... more Several single nucleotide variations (SNVs) affect carboxylesterase 1 (CES1) activity, but the effects of genetic variants on CES1 gene expression have not been systematically investigated. Therefore, our aim was to investigate effects of genetic variants on CES1 gene expression in two independent whole blood sample cohorts of 192 (discovery) and 88 (replication) healthy volunteers and in a liver sample cohort of 177 patients. Furthermore, we investigated possible effects of the found variants on clopidogrel pharmacokinetics (n = 106) and pharmacodynamics (n = 46) in healthy volunteers, who had ingested a single 300 mg or 600 mg dose of clopidogrel. Using massively parallel sequencing, we discovered two CES1 SNVs, rs12443580 and rs8192935, to be strongly and independently associated with a 39% (p = 4.0 × 10 ) and 31% (p = 2.5 × 10 ) reduction in CES1 whole blood expression per copy of the minor allele. These findings were replicated in the replication cohort. However, these SNVs did...
Journal of Biomechanical Engineering
The objective of the study was to investigate the effects of bariatric surgery-induced weight los... more The objective of the study was to investigate the effects of bariatric surgery-induced weight loss on knee gait and cartilage degeneration in osteoarthritis (OA) by combining magnetic resonance imaging (MRI), gait analysis, finite element (FE) modeling, and cartilage degeneration algorithm. Gait analyses were performed for obese subjects before and one-year after the bariatric surgery. FE models were created before and after weight loss for those subjects who did not have severe tibio-femoral knee cartilage loss. Knee cartilage degenerations were predicted using an adaptive cartilage degeneration algorithm which is based on cumulative overloading of cartilage, leading to iteratively altered cartilage properties during OA. The average weight loss was 25.7±11.0 kg corresponding to a 9.2±3.9 kg/m2 decrease in body mass index (BMI). External knee rotation moment increased, and minimum knee flexion angle decreased significantly (p
European journal of gastroenterology & hepatology, Sep 1, 2018
Fatty liver disease (FLD) has been identified as constituting cardiometabolic risk. However, evid... more Fatty liver disease (FLD) has been identified as constituting cardiometabolic risk. However, evidence on the association of fatty liver index (FLI) with cardiovascular disease (CVD) is largely cross-sectional, with limited evidence on the predictability of incident CVD, and specifically, acute myocardial infarction (AMI). Therefore, we aimed to investigate the prospective associations between fatty liver as estimated by FLI and incident CVD, and specifically AMI, in the Kuopio Ischaemic Heart Disease Risk Factor Study cohort. Our patients were 1205 middle-aged men free of CVD at baseline. The associations of baseline FLI with incident CVD and incident AMI were analyzed using multivariable-adjusted Cox regression models. During a median follow-up of 17 years, a total of 690 incident cases of CVD and 269 cases of AMI were recorded through Finnish registries. For incident CVD, for the high (FLI≥60) versus the low (≤30) FLI category, the hazard ratio (HR) was 1.77 [95% confidence interv...
Bioscience Reports
Background and aims: Non-alcoholic fatty liver disease (NAFLD) associates with low levels of seru... more 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.: MethodsOut of the 138 individuals (age: 46.3 ± 8.9, body mass index: 43.3 ± 6.9 kg/m², 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).: ResultsLiver and bile sitostanol ratios to cholesterol were higher in those with NAFLD compared to those with histologically normal liver (all P<0.022). F...
Hepatology communications, 2018
Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver damage and has a strong geneti... more Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver damage and has a strong genetic component. The rs4841132 G>A variant, modulating the expression of protein phosphatase 1 regulatory subunit 3B (), which is involved in glycogen synthesis, has been reported to reduce the risk of NAFLD but at the same time may favor liver disease by facilitating glycogen accumulation. The aim of this study was to assess the impact of rs4841132 on development of histologic steatosis and fibrosis in 1,388 European individuals in a liver biopsy cohort, on NAFLD hepatocellular carcinoma in a cross-sectional Italian cohort (n = 132 cases), and on liver disease at the population level in the United Kingdom Biobank cohort. We investigated the underlying mechanism by examining the impact of the variant on gene expression profiles. In the liver biopsy cohort, the rs4841132 minor A allele was associated with protection against steatosis (odds ratio [OR], 0.63; 95% confidence interval [CI], 0....
Genome Medicine
Background: Genome-wide association studies (GWAS) have identified more than 100 genetic loci ass... more Background: Genome-wide association studies (GWAS) have identified more than 100 genetic loci associated with type 2 diabetes (T2D). However, the underlying biological mechanisms for many of these associations remain unknown. GWAS signals close to the glucokinase regulatory protein gene (GCKR) have been reported for lipid and glucose metabolism traits and the risk of T2D. We investigated the regulatory function of an intronic locus at GCKR represented by the lead single nucleotide polymorphism (SNP) rs780094. Methods: We used ENCODE project histone modification and transcription factor binding data to determine the regulatory features of a GCKR intronic locus formed by the high linkage disequilibrium rs780094(C/T), rs780095(G/A), and rs780096(G/C) SNPs. Characterization of the transcriptional activity of this region was assessed by luciferase reporter assays in HepG2 cells and mouse primary hepatocytes. ChIP-qPCR was used to determine the levels of haplotype specific transcription factor binding and histone marks. A CRISPR-dCas9 transcriptional activator system and qPCR were used to activate the locus and measure GCKR expression, respectively. Differential haplotype expression was measured from human liver biopsies. Results: The ENCODE data suggest the existence of a liver-specific intragenic enhancer at the locus represented by s780094. We observed that FOXA2 increased the transcriptional activity of this region in a haplotype specific way (CGG > TAC; rs780094, rs780095, and rs780096). In addition, the CGG haplotype showed higher binding to FOXA2 and higher levels of the H3K27Ac histone mark. The epigenetic activation of this locus increased the expression of endogenous GCKR in HepG2 cells, confirming that GCKR is the direct target gene of the enhancer. Finally, we confirmed that the CGG haplotype exhibits higher levels of transcription in human liver. Conclusions: Our results demonstrate the existence of a liver-specific FOXA2-regulated transcriptional enhancer at an intronic T2D locus represented by rs780094, rs780095, and rs780096 SNPs that increases GCKR expression. Differential haplotype regulation suggests the existence of cis regulatory effects that may contribute to the associated traits at this locus.
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Papers by Jussi Pihlajamäki