Browsing by Subject "FATTY LIVER-DISEASE"

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  • Neuman, Manuela G.; French, Samuel W.; Zakhari, Samir; Malnick, Stephen; Seitz, Helmut K.; Cohen, Lawrence B.; Salaspuro, Mikko; Voinea-Griffin, Andreea; Barasch, Andrei; Kirpich, Irina A.; Thomes, Paul G.; Schrum, Laura W.; Donohue, Terrence M.; Kharbanda, Kusum K.; Cruz, Marcus; Opris, Mihai (2017)
    This paper is based upon the "8th Charles Lieber's Satellite Symposium" organized by Manuela G. Neuman at the Research Society on Alcoholism Annual Meeting, on June 25, 2016 at New Orleans, Louisiana, USA. The integrative symposium investigated different aspects of alcohol-induced liver disease (ALD) as well as non alcohol -induced liver disease (NAFLD) and possible repair. We revealed the basic aspects of alcohol metabolism that may be responsible for the development of liver disease as well as the factors that determine the amount, frequency and which type of alcohol misuse leads to liver and gastrointestinal diseases. We aimed to (1) describe the immuno-pathology of ALD, (2) examine the role of genetics in the development of alcoholic hepatitis (ASH) and NAFLD, (3) propose diagnostic markers of ASH and non-alcoholic steatohepatitis (NASH), (4) examine age and ethnic differences as well as analyze the validity of some models, (5) develop common research tools and biomarkers to study alcohol-induced effects, 6) examine the role of alcohol in oral health and colon and gastrointestinal cancer and (7) focus on factors that aggravate the severity of organ-damage. The present review includes pre-clinical, translational and clinical research that characterizes ALD and NAFLD. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD with simple fatty infiltrations and chronic alcoholic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular.and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes and cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human deficiency virus were discussed. Dysregulation of metabolism, as a result of ethanol exposure, in the intestine leads to colon carcinogenesis. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota have been suggested. The clinical aspects of NASH, as part of the metabolic syndrome in the aging population, have been presented. The symposium addressed mechanisms and biomarkers of alcohol induced damage to different organs, as well as the role of the microbiome in this dialog. The microbiota regulates and acts as a key element in harmonizing immune responses at intestinal mucosal surfaces. It is known that microbiota is an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. The signals at the sites of inflammation mediate recruitment and differentiation in order to remove inflammatory inducers and promote tissue homeostasis restoration. The change in the intestinal microbiota also influences the change in obesity and regresses the liver steatosis. Evidence on the positive role of moderate alcohol consumption on heart and metabolic diseases as well on reducing steatosis have been looked up. Moreover nutrition as a therapeutic intervention in alcoholic liver disease has been discussed. In addition to the original data, we searched the literature (2008-2016) for the latest publication on the described subjects. In order to obtain the updated data we used the usual engines (Pub Med and Google Scholar). The intention of the eighth symposia was to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism. (C) 2017 Elsevier Inc. All rights reserved.
  • Latorre, Jèssica; Ortega, Francisco J.; Liñares-Pose, Laura; Moreno-Navarrete, José M.; Lluch, Aina; Comas, Ferran; Oliveras-Cañellas, Núria; Ricart, Wifredo; Höring, Marcus; Zhou, You; Liebisch, Gerhard; Nidhina Haridas, P.A.; Olkkonen, Vesa M.; López, Miguel; Fernández-Real, José M. (2020)
    Background: While the impact of metformin in hepatocytes leads to fatty acid (FA) oxidation and decreased lipogenesis, hepatic microRNAs (miRNAs) have been associated with fat overload and impaired metabolism, contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Methods: We investigated the expression of hundreds of miRNAs in primary hepatocytes challenged by compounds modulating steatosis, palmitic acid and compound C (as inducers), and metformin (as an inhibitor). Then, additional hepatocyte and rodent models were evaluated, together with transient mimic miRNAs transfection, lipid droplet staining, thin-layer chromatography, quantitative lipidomes, and mitochondrial activity, while human samples outlined the translational significance of this work. Findings: Our results show that treatments triggering fat accumulation and AMPK disruption may compromise the biosynthesis of hepatic miRNAs, while the knockdown of the miRNA-processing enzyme DICER in human hepatocytes exhibited increased lipid deposition. In this context, the ectopic recovery of miR-30b and miR-30c led to significant changes in genes related to FA metabolism, consistent reduction of ceramides, higher mitochondrial activity, and enabled b-oxidation, redirecting FA metabolism fromenergy storage to expenditure. Interpretation: Current findings unravel the biosynthesis of hepatic miR-30b and miR-30c in tackling inadequate FA accumulation, offering a potential avenue for the treatment of NAFLD. Funding: Instituto de Salud Carlos III (ISCIII), Govern de la Generalitat (PERIS2016), Associacio Catalana de Diabetis (ACD), Sociedad Espanola de Diabetes (SED), Fondo Europeo de Desarrollo Regional (FEDER), Xunta de Galicia, Ministerio de Economia y Competitividad (MINECO), "La Caixa" Foundation, and CIBER de la Fisiopatologia de la Obesidad y Nutricion (CIBEROBN). (c) 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. (
  • 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.
  • Heiskanen, Jarkko S.; Ruohonen, Saku; Rovio, Suvi P.; Kytö, Ville; Kähönen, Mika; Lehtimäki, Terho; Viikari, Jorma S. A.; Juonala, Markus; Laitinen, Tomi; Tossavainen, Päivi; Jokinen, Eero; Hutri-Kähönen, Nina; Raitakari, Olli T. (2019)
    Decreased left ventricular (LV) diastolic function is associated with increased all-cause mortality and risk for a heart failure. The determinants of LV diastolic function have been mainly studied in elderly populations; however, the origin of LV heart failure may relate to the lifestyle factors acquired during the life course. Therefore, we examined biochemical, physiological, and lifestyle determinants of LV diastolic function in 34-49-year-old participants of the Cardiovascular Risk in Young Finns Study (Young Finns Study). In 2011, clinical examination and echocardiography were performed for 1928 participants (880 men and 1048 women; aged 34-49 years). LV diastolic function was primarily defined using E/e-ratio (population mean 4.8, range 2.1-9.0). In a multivariate model, systolic blood pressure (P <0.005), female sex (P <0.005), age (P <0.005), waist circumference (P = 0.024), smoking (P = 0.028), serum alanine aminotransferase (P = 0.032) were directly associated with E/e-ratio, while an inverse association was found for height (P <0.005). Additionally, a higher E/e-ratio was found in participants with concentric hypertrophy compared to normal cardiac geometry (P <0.005). Other indicators of the LV diastolic function including E/A-ratio and left atrial volume index showed similarly strong associations with systolic blood pressure and age. In conclusion, we identified systolic blood pressure, waist circumference and smoking as modifiable determinants of the LV diastolic function in the 34-49-year-old participants of the Young Finns Study.
  • Taskinen, Marja-Riitta; Packard, Chris J.; Boren, Jan (2019)
    Consumption of fructose, the sweetest of all naturally occurring carbohydrates, has increased dramatically in the last 40 years and is today commonly used commercially in soft drinks, juice, and baked goods. These products comprise a large proportion of the modern diet, in particular in children, adolescents, and young adults. A large body of evidence associate consumption of fructose and other sugar-sweetened beverages with insulin resistance, intrahepatic lipid accumulation, and hypertriglyceridemia. In the long term, these risk factors may contribute to the development of type 2 diabetes and cardiovascular diseases. Fructose is absorbed in the small intestine and metabolized in the liver where it stimulates fructolysis, glycolysis, lipogenesis, and glucose production. This may result in hypertriglyceridemia and fatty liver. Therefore, understanding the mechanisms underlying intestinal and hepatic fructose metabolism is important. Here we review recent evidence linking excessive fructose consumption to health risk markers and development of components of the Metabolic Syndrome.
  • Witjes, Julia J.; Smits, Loek P.; Pekmez, Ceyda T.; Prodan, Andrei; Meijnikman, Abraham S.; Troelstra, Marian A.; Bouter, Kristien E. C.; Herrema, Hilde; Levin, Evgeni; Holleboom, Adriaan G.; Winkelmeijer, Maaike; Beuers, Ulrich H.; van Lienden, Krijn; Aron-Wisnewky, Judith; Mannisto, Ville; Bergman, Jacques J.; Runge, Jurgen H.; Nederveen, Aart J.; Dragsted, Lars O.; Konstanti, Prokopis; Zoetendal, Erwin G.; de Vos, Willem; Verheij, Joanne; Groen, Albert K.; Nieuwdorp, Max (2020)
    The intestinal microbiota has been linked to the development and prevalence of steatohepatitis in humans. Interestingly, steatohepatitis is significantly lower in individuals taking a plant-based, low-animal-protein diet, which is thought to be mediated by gut microbiota. However, data on causality between these observations in humans is scarce. In this regard, fecal microbiota transplantation (FMT) using healthy donors is safe and is capable of changing microbial composition in human disease. We therefore performed a double-blind randomized controlled proof-of-principle study in which individuals with hepatic steatosis on ultrasound were randomized to two study arms: lean vegan donor (allogenic n = 10) or own (autologous n = 11) FMT. Both were performed three times at 8-week intervals. A liver biopsy was performed at baseline and after 24 weeks in every subject to determine histopathology (Nonalcoholic Steatohepatitis Clinical Research Network) classification and changes in hepatic gene expression based on RNA sequencing. Secondary outcome parameters were changes in intestinal microbiota composition and fasting plasma metabolomics. We observed a trend toward improved necro-inflammatory histology, and found significant changes in expression of hepatic genes involved in inflammation and lipid metabolism following allogenic FMT. Intestinal microbial community structure changed following allogenic FMT, which was associated with changes in plasma metabolites as well as markers of .Conclusion:Allogenic FMT using lean vegan donors in individuals with hepatic steatosis shows an effect on intestinal microbiota composition, which is associated with beneficial changes in plasma metabolites and markers of steatohepatitis.
  • Boren, Jan; Adiels, Martin; Bjornson, Elias; Matikainen, Niina; Söderlund, Sanni; Rämö, Joel; Ståhlman, Marcus; Ripatti, Pietari; Ripatti, Samuli; Palotie, Aarno; Mancina, Rosellina M.; Hakkarainen, Antti; Romeo, Stefano; Packard, Chris J.; Taskinen, Marja-Riitta (2020)
    Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation. The transmembrane 6 superfamily member 2 (TM6SF2) E167K genetic variant associates with NAFLD and with reduced plasma triglyceride levels in humans. However, the molecular mechanisms underlying these associations remain unclear. We hypothesized that TM65F2 E167K affects hepatic very low-density lipoprotein (VLDL) secretion and studied the kinetics of apolipoprotein 13100 (apoB100) and triglyceride metabolism in VLDL in homozygous subjects. In 10 homozygote TM6SF2 E167K carriers and 10 matched controls, we employed stable-isotope tracer and compartmental modeling techniques to determine apoB100 and triglyceride kinetics in the 2 major VIOL subtractions: large triglyceride-rich VLDL, and smaller, less triglyceride-rich VLDL2. VLDL1-apoB100 production was markedly reduced in homozygote TM6SF2 E167K carriers compared with controls. Likewise. VLDL,-triglyceride production was 35% lower in the TMSSF2 E167K carriers. In contrast, the direct production rates for VLDL2 apo13100 and triglyceride were not different between carriers and controls. In conclusion, the TM6SF2 E167K genetic variant was linked to a specific reduction in hepatic secretion of large triglyceride-rich VLDL1. The impaired secretion of VLDL1 explains the reduced plasma triglyceride concentration and provides a basis for understanding the lower risk of cardiovascular disease associated with the TM6SF2 E167K genetic variant.
  • Hoekstra, Menno; Ren, Baoyan; Laurila, Pirkka-Pekka; Hildebrand, Reeni B.; Soronen, Jarkko; Frodermann, Vanessa; Li, Zhuang; Boon, Mariette R.; Geerling, Janine J.; Rensen, Patrick C. N.; Jauhiainen, Matti; Van Eck, Miranda (2021)
    Total body upstream stimulatory factor 1 (USF1) deficiency in mice is associated with brown adipose tissue activation and a marked protection against the development of obesity and atherosclerotic lesions. Functional expression of USF1 has also been detected in monocytes and monocyte-derived macrophages. In the current study we therefore tested whether selective hematopoietic USF1 deficiency can also beneficially impact the development of atherosclerosis. For this purpose, LDL receptor knockout mice were transplanted with bone marrow from USF1 knockout mice or their wild-type littermate controls and subsequently fed a Western-type diet for 20 weeks to stimulate atherosclerotic lesion development. Strikingly, absence of USF1 function in bone marrow-derived cells was associated with exacerbated blood leukocyte (+ 100%; P < 0.01) and peritoneal leukocyte (+ 50%; P < 0.05) lipid loading and an increased atherosclerosis susceptibility (+ 31%; P < 0.05). These effects could be attributed to aggravated hyperlipidemia, i.e. higher plasma free cholesterol (+ 33%; P < 0.001) and cholesteryl esters (+ 39%; P < 0.001), and the development of hepatosteatosis. In conclusion, we have shown that hematopoietic USF1 deficiency is associated with an increased atherosclerosis susceptibility in LDL receptor knockout mice. These findings argue against a contribution of macrophage-specific USF1 deficiency to the previously described beneficial effect of total body USF1 deficiency on atherosclerosis susceptibility in mice.
  • Laitakari, Anna; Tapio, Joona; Mäkelä, Kari A.; Herzig, Karl-Heinz; Dengler, Franziska; Gylling, Helena; Walkinshaw, Gail; Myllyharju, Johanna; Dimova, Elitsa Y.; Serpi, Raisa; Koivunen, Peppi (2020)
    Non-alcoholic fatty liver disease (NAFLD) parallels the global obesity epidemic with unmet therapeutic needs. We investigated whether inhibition of hypoxia-inducible factor prolyl 4-hydroxylase-2 (HIF-P4H-2), a key cellular oxygen sensor whose inhibition stabilizes HIF, would protect from NAFLD by subjecting HIF-P4H-2-deficient (Hif-p4h-2(gt/gt)) mice to a high-fat, high-fructose (HFHF) or high-fat, methionine-choline-deficient (HF-MCD) diet. On both diets, the Hif-p4h-2(gt/gt) mice gained less weight and had less white adipose tissue (WAT) and its inflammation, lower serum cholesterol levels, and lighter livers with less steatosis and lower serum ALT levels than the wild type (WT). The intake of fructose in majority of the Hif-p4h-2(gt/gt) tissues, including the liver, was 15-35% less than in the WT. We found upregulation of the key fructose transporter and metabolizing enzyme mRNAs, Slc2a2, Khka, and Khkc, and higher ketohexokinase activity in the Hif-p4h-2(gt/gt) small intestine relative to the WT, suggesting enhanced metabolism of fructose in the former. On the HF-MCD diet, the Hif-p4h-2(gt/gt) mice showed more browning of the WAT and increased thermogenesis. A pharmacological pan-HIF-P4H inhibitor protected WT mice on both diets against obesity, metabolic dysfunction, and liver damage. These data suggest that HIF-P4H-2 inhibition could be studied as a novel, comprehensive treatment strategy for NAFLD. Key messages center dot HIF-P4H-2 inhibition enhances intestinal fructose metabolism protecting the liver. center dot HIF-P4H-2 inhibition downregulates hepatic lipogenesis. center dot Induced browning of WAT and increased thermogenesis can also mediate protection. center dot HIF-P4H-2 inhibition offers a novel, comprehensive treatment strategy for NAFLD.
  • 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.
  • Mannisto, Ville T.; Simonen, Marko; Soininen, Pasi; Tiainen, Mika; Kangas, Antti J.; Kaminska, Dorota; Venesmaa, Sari; Kakela, Pirjo; Karja, Vesa; Gylling, Helena; Ala-Korpela, Mika; Pihlajamaki, Jussi (2014)
  • Matikainen, Niina; Söderlund, Sanni; Björnson, Elias; Pietiläinen, Kirsi; Hakkarainen, Antti; Lundbom, Nina; Taskinen, Marja-Riitta; Boren, Jan (2019)
    Aims Patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) exhibit considerable residual risk for cardiovascular disease (CVD). There is, therefore, increasing interest in targeting postprandial lipid metabolism and remnant cholesterol. Treatment with the glucagon-like peptide 1 (GLP-1) analogue liraglutide reduces CVD risk by mechanisms that remain unexplained in part. Here we investigated the effects of liraglutide intervention on ectopic fat depots, hepatic lipogenesis and fat oxidation, postprandial lipid metabolism and glycaemia in humans with type 2 diabetes. Methods The effect of liraglutide was investigated in 22 patients with adequately controlled type 2 diabetes. Patients were randomly allocated, in a single-blind fashion, to either liraglutide 1.8 mg or placebo once daily for 16 weeks. Because liraglutide is known to promote weight loss, the study included dietary counselling to achieve similar weight loss in the liraglutide and placebo groups. Cardiometabolic responses to a high-fat mixed meal were measured before and at the end of the liraglutide intervention. Results Weight loss at Week 16 was similar between the groups: -2.4 kg (-2.5%) in the liraglutide group and -2.1 kg (-2.2%) in the placebo group. HBA1c improved by 6.4 mmol/mol (0.6%) in the liraglutide group (P = 0.005). Liver fat decreased in both groups, by 31% in the liraglutide group and by 18% in the placebo group, but there were no significant changes in the rate of hepatic de novo lipogenesis or beta-hydroxybutyrate levels, a marker of fat oxidation. We observed significant postprandial decreases in triglycerides only in plasma, chylomicrons and VLDL, and remnant particle cholesterol after treatment in the liraglutide group. Fasting and postprandial apoCIII concentrations decreased after liraglutide intervention and these changes were closely related to reduced glycaemia. In relative importance analysis, approximately half of the changes in postprandial lipids were explained by reductions in apoCIII concentrations, whereas less than 10% of the variation in postprandial lipids was explained by reductions in weight, glycaemic control, liver fat or postprandial insulin responses. Conclusions Intervention with liraglutide for 16 weeks produces multiple improvements in cardiometabolic risk factors that were not seen in the placebo group, despite similar weight loss. Of particular importance was a marked reduction in postprandial atherogenic remnant particles. The underlying mechanism may be improved glycaemic control, which leads to reduced expression of apoCIII, a key regulator of hypertriglyceridaemia in hyperglycaemic patients.
  • Tanaka, Yuki; Shimanaka, Yuta; Caddeo, Andrea; Kubo, Takuya; Mao, Yanli; Kubota, Tetsuya; Kubota, Naoto; Yamauchi, Toshimasa; Mancina, Rosellina Margherita; Baselli, Guido; Luukkonen, Panu; Pihlajamäki, Jussi; Yki-Järvinen, Hannele; Valenti, Luca; Arai, Hiroyuki; Romeo, Stefano; Kono, Nozomu (2021)
    Objective Non-alcoholic fatty liver disease (NAFLD) is a common prelude to cirrhosis and hepatocellular carcinoma. The genetic rs641738 C>T variant in the lysophosphatidylinositol acyltransferase 1 (LPIAT1)/membrane bound O-acyltransferase domain-containing 7, which incorporates arachidonic acid into phosphatidylinositol (PI), is associated with the entire spectrum of NAFLD. In this study, we investigated the mechanism underlying this association in mice and cultured human hepatocytes. Design We generated the hepatocyte-specific Lpiat1 knockout mice to investigate the function of Lpiat1 in vivo. We also depleted LPIAT1 in cultured human hepatic cells using CRISPR-Cas9 systems or siRNA. The effect of LPIAT1-depletion on liver fibrosis was examined in mice fed high fat diet and in liver spheroids. Lipid species were measured using liquid chromatography-electrospray ionisation mass spectrometry. Lipid metabolism was analysed using radiolabeled glycerol or fatty acids. Results The hepatocyte-specific Lpiat1 knockout mice developed hepatic steatosis spontaneously, and hepatic fibrosis on high fat diet feeding. Depletion of LPIAT1 in cultured hepatic cells and in spheroids caused triglyceride accumulation and collagen deposition. The increase in hepatocyte fat content was due to a higher triglyceride synthesis fueled by a non-canonical pathway. Indeed, reduction in the PI acyl chain remodelling caused a high PI turnover, by stimulating at the same time PI synthesis and breakdown. The degradation of PI was mediated by a phospholipase C, which produces diacylglycerol, a precursor of triglyceride. Conclusion We found a novel pathway fueling triglyceride synthesis in hepatocytes, by a direct metabolic flow of PI into triglycerides. Our findings provide an insight into the pathogenesis and therapeutics of NAFLD.
  • Ganel, Liron; Chen, Lei; Christ, Ryan; Vangipurapu, Jagadish; Young, Erica; Das, Indraniel; Kanchi, Krishna; Larson, David; Regier, Allison; Abel, Haley; Kang, Chul Joo; Scott, Alexandra; Havulinna, Aki; Chiang, Charleston W. K.; Service, Susan; Freimer, Nelson; Palotie, Aarno; Ripatti, Samuli; Kuusisto, Johanna; Boehnke, Michael; Laakso, Markku; Locke, Adam; Stitziel, Nathan O.; Hall, Ira M. (2021)
    Background Mitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood. When measured by bulk DNA sequencing in blood, MT-CN may reflect a combination of the number of mitochondria per cell and cell-type composition. Here, we studied MT-CN variation in blood-derived DNA from 19184 Finnish individuals using a combination of genome (N = 4163) and exome sequencing (N = 19034) data as well as imputed genotypes (N = 17718). Results We identified two loci significantly associated with MT-CN variation: a common variant at the MYB-HBS1L locus (P = 1.6 x 10(-8)), which has previously been associated with numerous hematological parameters; and a burden of rare variants in the TMBIM1 gene (P = 3.0 x 10(-8)), which has been reported to protect against non-alcoholic fatty liver disease. We also found that MT-CN is strongly associated with insulin levels (P = 2.0 x 10(-21)) and other metabolic syndrome (metS)-related traits. Using a Mendelian randomization framework, we show evidence that MT-CN measured in blood is causally related to insulin levels. We then applied an MT-CN polygenic risk score (PRS) derived from Finnish data to the UK Biobank, where the association between the PRS and metS traits was replicated. Adjusting for cell counts largely eliminated these signals, suggesting that MT-CN affects metS via cell-type composition. Conclusion These results suggest that measurements of MT-CN in blood-derived DNA partially reflect differences in cell-type composition and that these differences are causally linked to insulin and related traits.
  • Mattila, Jaakko; Havula, Essi; Suominen, Erja; Teesalu, Mari; Surakka, Ida; Hynynen, Riikka; Kilpinen, Helena; Vaananen, Juho; Hovatta, Iiris; Kakela, Reijo; Ripatti, Samuli; Sandmann, Thomas; Hietakangas, Ville (2015)
    The ChREBP/Mondo-Mlx transcription factors are activated by sugars and are essential for sugar tolerance. They promote the conversion of sugars to lipids, but beyond this, their physiological roles are insufficiently understood. Here, we demonstrate that in an organism-wide setting in Drosophila, Mondo-Mlx controls the majority of sugar-regulated genes involved in nutrient digestion and transport as well as carbohydrate, amino acid, and lipid metabolism. Furthermore, human orthologs of the Mondo-Mlx targets display enrichment among gene variants associated with high circulating triglycerides. In addition to direct regulation of metabolic genes, Mondo-Mlx maintains metabolic homeostasis through downstream effectors, including the Activin ligand Dawdle and the Gli-similar transcription factor Sugarbabe. Sugarbabe controls a subset of Mondo-Mlx-dependent processes, including de novo lipogenesis and fatty acid desaturation. In sum, Mondo-Mlx is a master regulator of other sugar-responsive pathways essential for adaptation to a high-sugar diet.
  • 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.
  • Pirinen, Eija; Auranen, Mari; Khan, Nahid A.; Brilhante, Virginia; Urho, Niina; Pessia, Alberto; Hakkarainen, Antti; Kuula, Juho; Heinonen, Ulla; Schmidt, Mark S.; Haimilahti, Kimmo; Piirilä, Päivi; Lundbom, Nina; Taskinen, Marja-Riitta; Brenner, Charles; Velagapudi, Vidya; Pietiläinen, Kirsi H.; Suomalainen, Anu (2020)
    NAD(+) is a redox-active metabolite, the depletion of which has been proposed to promote aging and degenerative diseases in rodents. However, whether NAD(+) depletion occurs in patients with degenerative disorders and whether NAD(+) repletion improves their symptoms has remained open. Here, we report systemic NAD(+) deficiency in adult-onset mitochondrial myopathy patients. We administered an increasing dose of NAD(+) booster niacin, a vitamin B3 form (to 750-1,000 mg/day; NCT03973203) for patients and their matched controls for 10 or 4 months, respectively. Blood NAD(+) increased in all subjects, up to 8-fold, and muscle-NAD(+) of patients reached the level of their controls. Some patients showed anemia tendency, while muscle strength and mitochondrial biogenesis increased in all subjects. In patients, muscle metabolome shifted toward controls and liver fat decreased even 50%. Our evidence indicates that blood analysis is useful in identifying NAD(+) deficiency and points niacin to be an efficient NAD(+) booster for treating mitochondrial myopathy.
  • Mardinoglu, Adil; Bjornson, Elias; Zhang, Cheng; Klevstig, Martina; Söderlund, Sanni; Ståhlman, Marcus; Adiels, Martin; Hakkarainen, Antti; Lundbom, Nina; Kilicarslan, Murat; Hallström, Björn M.; Lundbom, Jesper; Verges, Bruno; Barrett, Peter Hugh R.; Watts, Gerald F.; Serlie, Mireille J.; Nielsen, Jens; Uhlen, Mathias; Smith, Ulf; Marschall, Hanns-Ulrich; Taskinen, Marja-Riitta; Boren, Jan (2017)
    To elucidate the molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome-scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD(+) and glutathione (GSH) in subjects with high HS. Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD(+) repletion on the development of NAFLD, we added precursors for GSH and NAD(+) biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof-of-concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.
  • Eskelinen, Saana; Suvisaari, Janne V. J.; Suvisaari, Jaana M. (2020)
    Background Guidelines on laboratory screening in schizophrenia recommend annual monitoring of fasting lipids and glucose. The utility and the cost effectiveness of more extensive laboratory screening have not been studied. Methods The Living Conditions and the Physical Health of Outpatients with Schizophrenia Study provided a comprehensive health examination, including a laboratory test panel for 275 participants. We calculated the prevalence of the results outside the reference range for each laboratory test, and estimated the cost effectiveness to find an aberrant test result using the number needed to screen to find one abnormal result (NNSAR) and the direct cost spent to find one abnormal result (DCSAR, NNSAR x direct cost per test) formulas. In addition, we studied whether patients who were obese or used clozapine had more often abnormal results. Results A half of the sample had 25-hydroxyvitamin D below, and almost one-fourth cholesterol, triglycerides or glucose above the reference range. One-fifth had sodium below and gamma glutamyltransferase above the reference range. NNSAR was highest for potassium (137) and lowest for 25-hydroxyvitamin D (2). DCSAR was below 5euro for glucose, all lipids and sodium, and below 10euro for creatinine and gamma glutamyltransferase. Potassium (130euro), pH-adjusted ionized calcium (33 euro) and thyroid stimulating hormone (33euro) had highest DCSARs. Several abnormal results were more common in obese and clozapine using patients. Conclusions An annual laboratory screening panel for an outpatient with schizophrenia should include fasting glucose, lipids, sodium, creatinine, a liver function test and complete blood count, and preferably 25-hydroxyvitamin D.
  • Ruhanen, Hanna; Perttila, Julia; Holtta-Vuori, Maarit; Zhou, You; Yki-Jarvinen, Hannele; Ikonen, Elina; Kakela, Reijo; Olkkonen, Vesa M. (2014)