Minerva Foundation Institute for Medical Research

Helsinki, Finland

Minerva Foundation Institute for Medical Research

Helsinki, Finland
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Zhou Y.,Minerva Foundation Institute for Medical Research | Llaurado G.,Minerva Foundation Institute for Medical Research | Llaurado G.,Rovira i Virgili University | Oresic M.,Steno Diabetes Center | And 4 more authors.
Journal of Hepatology | Year: 2015

Background & Aims The Glu167Lys (E167K) variant in the transmembrane 6 superfamily member 2 protein (TM6SF2) was recently shown to influence liver fat (LFAT) content. We aimed at studying how this variant influences circulating triacylglycerol (TAG) signatures and whether it influences hepatic or adipose tissue insulin sensitivity. Methods We genotyped 300 Finnish subjects for the E167K (rs58542926) variant in TM6SF2 and for the I148M (rs738409) variant in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) in whom LFAT was measured using 1H-MRS and circulating lipids by UPLC-MS. We compared the plasma lipidome between E167K carriers (TM6SF2EK/KK) and non-carriers (TM6SF2EE), and between three groups of NAFLD: (i) carriers of the E167K but not of the I148M variant in PNPLA3 ('TM6SF2 NAFLD'), (ii) carriers of the I148M but not of the E167K variant ('PNPLA3 NAFLD'), and (iii) non-carriers of either risk allele ('Non-risk NAFLD'). Hepatic and adipose tissue insulin sensitivities were measured using the euglycemic hyperinsulinemic clamp technique combined with infusion of [3-3H]glucose in 111 subjects. Results The LFAT content was 34% higher in the TM6SF2EK/KK (13.07 ± 1.57%) than in the TM6SF2EE group (9.77 ± 0.58%, p = 0.013). The effect of insulin on glucose production and lipolysis were significantly higher in the TM6SF2EK/KK than in the TM6SF2EE group. Comparison of the three NAFLD groups with similar LFATs showed that both the 'TM6SF2 NAFLD' and 'PNPLA3 NAFLD' had significantly lower triglyceride levels and were characterized by lower levels of most common TAGs compared to the 'Non-risk NAFLD' group. Conclusions We conclude that the E167K variant in TM6SF2 is associated with a distinct subtype of NAFLD, characterized by preserved insulin sensitivity with regard to lipolysis, hepatic glucose production and lack of hypertriglyceridemia despite a clearly increased LFAT content. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Brown A.J.,University of New South Wales | Ikonen E.,University of Helsinki | Ikonen E.,Minerva Foundation Institute for Medical Research | Olkkonen V.M.,Minerva Foundation Institute for Medical Research
Current Opinion in Lipidology | Year: 2014

PURPOSE OF REVIEW: Circulating levels of cholesterol precursors in the body have proven their value over the years as indicators of in-vivo cholesterol synthesis. However, there is growing interest in their potential as markers of various disease states. The purpose of this review is to evaluate current literature on cholesterol precursors as disease markers. RECENT FINDINGS: Firstly, we focus on studies linking circulating squalene with the risk of cardiovascular disease. Secondly, we explore the interplay between cholesterol precursors (7-dehydrocholesterol and desmosterol) and the enzymes that act upon them (DHCR7 and DHCR24) in the context of liver disease. For instance, recent findings indicate that circulating desmosterol is elevated in nonalcoholic steatohepatitis. This may be linked to this regulatory cholesterol precursor being produced in and effluxed from hepatocytes, or alternatively from lipid-laden hepatic macrophages (Kupffer cells), which play an important role in the cause of nonalcoholic steatohepatitis. Desmosterol is also implicated in Hepatitis C virus replication, and hence may also be involved in viral fatty liver disease, possibly contributing to virus pathogenicity and/or host defense. Furthermore, there is increasing evidence that the activity of DHCR7 may affect chronic liver diseases by influencing vitamin D levels. SUMMARY: Beyond their accepted application as markers of cholesterol synthesis, cholesterol precursors have potential both as disease indicators, and for providing deeper insights into the disease process. © 2014 Wolters Kluwer Health Lippincott Williams & Wilkins.


Yki-Jarvinen H.,University of Helsinki | Yki-Jarvinen H.,Minerva Foundation Institute for Medical Research
Diabetologia | Year: 2016

Non-alcoholic fatty liver disease (NAFLD) increases risk of mortality from liver and cardiovascular disease (CVD) and is the major cause of hepatocellular carcinoma (HCC), which may develop without cirrhosis. NAFLD predicts type 2 diabetes, even independently of obesity. Globally, the prevalence of NAFLD averages 25% and is as common as the metabolic syndrome. The majority of patients with type 2 diabetes have NAFLD. The challenge for the diabetologist is to identify patients at risk of advanced liver disease and HCC. At a minimum, liver function tests (LFTs), despite being neither specific nor sensitive, should be performed in all patients with the metabolic syndrome or type 2 diabetes. Increases in LFTs, for which the updated reference values are lower (serum ALT ≈30 U/l in men and ≈20 U/l in women) than those hitherto used in many laboratories, should prompt assessment of fibrosis biomarkers and referral of individuals at risk to a NAFLD/hepatology clinic. Preferably, evaluation of NAFLD should be based on measurement of steatosis biomarkers or ultrasound if easily available. A large number of individuals carry the patatin-like phospholipase domain containing 3 (PNPLA3) I148M variant (30–50%) or the transmembrane 6 superfamily member 2 (TM6SF2) E167K variant (11–15%). These variants increase the risk of advanced liver disease and HCC but not of diabetes or CVD. Genotyping of selected patients for these variants is recommended. Many patients have ‘double trouble’, i.e. carry both a genetic risk factor and have the metabolic syndrome. Excess use of alcohol could be a cause of ‘triple trouble’, but such patients would be classified as having alcoholic fatty liver disease. This review summarises a presentation given at the symposium ‘The liver in focus’ at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Kenneth Cusi, DOI: 10.1007/s00125-016-3952-1, and by John Jones, DOI: 10.1007/s00125-016-3940-5) and a commentary by the Session Chair, Michael Roden (DOI: 10.1007/s00125-016-3911-x). © 2016, Springer-Verlag Berlin Heidelberg.


Olkkonen V.M.,Minerva Foundation Institute for Medical Research | Olkkonen V.M.,University of Helsinki
Molecules | Year: 2013

Oxysterol-binding protein (OSBP) and its homologs designated OSBP-related (ORP) or OSBP-like (OSBPL) proteins constitute a conserved family of lipid binding/transfer proteins (LTP) in eukaryotes. The mechanisms of ORP function have remained incompletely understood, but they have been implicated as intracellular sterol sensors or transporters. A number of studies have provided evidence for the roles of ORPs at membrane contact sites (MCS), where endoplasmic reticulum is closely apposed with other organelle limiting membranes. ORPs are postulated to either transport sterols over MCSs or control the activity of enzymatic effectors or assembly of protein complexes with functions in signaling and lipid metabolism. Studies of yeast Saccharomyces cerevisiae ORPs Osh4p, Osh3p, Osh6p and Osh7p have revealed that ORPs do not exclusively bind sterols within their OSBP-related ligand-binding domain (ORD): The Osh4p ORD accommodates either sterols or phosphatidylinositol-4-phosphate (PI4P), and the Osh3p ORD was shown to specifically bind PI4P, the binding cavity being too narrow for a sterol to fit in. Most recently, Osh6p and Osh7p were demonstrated to show specific affinity for phosphatidylserine (PS), and to play a role in the intracellular transport of this glycerophospholipid; Additionally, two mammalian ORPs were shown to bind PS. Thus, the term frequently used for ORPs/OSBPLs, oxysterol-binding proteins, is a misnomer. While a number of ORPs bind oxysterols or cholesterol, other family members appear to interact with phospholipid ligands to regulate lipid fluxes, organelle lipid compositions and cell signaling. As a conclusion, ORPs are LTPs with a wide ligand spectrum and marked functional heterogeneity. © 2013 by the authors.


Zerenturk E.J.,University of New South Wales | Sharpe L.J.,University of New South Wales | Sharpe L.J.,University of Sydney | Ikonen E.,University of Helsinki | And 2 more authors.
Progress in Lipid Research | Year: 2013

3β-Hydroxysterol Δ24-reductase (DHCR24) catalyzes the conversion of desmosterol to cholesterol. This ultimate step of cholesterol biosynthesis appears to be remarkable in its diverse functions and the number of diseases it is implicated in from vascular disease to Hepatitis C virus (HCV) infection to cancer to Alzheimer's disease. This review summarizes the present knowledge on the DHCR24 gene, sterol Δ24-reductase protein and the regulation of both. In addition, the functions of desmosterol, DHCR24 and their roles in human diseases are discussed. It is apparent that DHCR24 exerts more complex effects than what would be expected based on the enzymatic activity of sterol Δ24-reduction alone, such as its influence in modulating oxidative stress. Increasing information about DHCR24 membrane association, processing, enzymatic regulation and interaction partners will provide further fundamental insights into DHCR24 and its many and varied biological roles. © 2013 Elsevier Ltd. All rights reserved.


Olkkonen V.M.,Minerva Foundation Institute for Medical Research | Olkkonen V.M.,University of Helsinki | Li S.,Minerva Foundation Institute for Medical Research | Li S.,University of Helsinki
Progress in Lipid Research | Year: 2013

Oxysterol-binding protein (OSBP) and OSBP-related proteins (ORPs) constitute a family of sterol and phosphoinositide binding proteins conserved in eukaryotes. The mechanisms of ORP function have remained incompletely understood. However, several ORPs are present at membrane contact sites and control the activity of enzymatic effectors or assembly of protein complexes, with impacts on signaling, vesicle transport, and lipid metabolism. An increasing number of protein interaction partners of ORPs have been identified, providing clues of their involvement in multiple aspects of cell regulation. The functions assigned for mammalian ORPs include coordination of sterol and sphingolipid metabolism and mitogenic signaling (OSBP), control of ER-late endosome (LE) contacts and LE motility (ORP1L), neutral lipid metabolism (ORP2), cell adhesion (ORP3), cholesterol eggress from LE (ORP5), macrophage lipid homeostasis, migration and high-density lipoprotein metabolism (ORP8), apolipoprotein B-100 secretion (ORP10), and adipogenesis (ORP11). The anti-proliferative ORPphilin compounds target OSBP and ORP4, revealing a function of ORPs in cell proliferation and survival. The Saccharomyces cerevisiae OSBP homologue (Osh) proteins execute multifaceted functions in sterol and sphingolipid homeostasis, post-Golgi vesicle transport, as well as phosphatidylinositol-4-phosphate and target of rapamycin complex 1 (TORC1) signaling. These observations identify ORPs as coordinators of lipid signals with an unforeseen variety of cellular processes. © 2013 Elsevier Ltd. All rights reserved.


Grasbeck R.,Minerva Foundation Institute for Medical Research
Biochimie | Year: 2013

In our pioneering work in 1956, two binders of vitamin B12 (B12) alias cobalamin (Cbl) were identified in gastric juice, S with slow electrophoretic mobility, a 70 kD protein with intrinsic factor (IF) activity and another rapid (R), not IF active but probable digestion product. Numerous sources contained a protein immunologically identical to R (haptocorrin, Hc). Another IF-active component (I) was found. Isoelectric focusing showed that S, I and R were assemblies of "isoproteins" with different pI's due to varying glycosidation. Isolation of S, I and R in microquantities was achieved in 1962 using a series of ion exchange chromatographies and gel filtration. Ponderable products were obtained in 1965-1966. The B12-IF complex was a dimer, contained 13% carbohydrate and showed a different absorption spectrum than B12. Using the Schilling test, B12 absorption was shown to require Ca++, bound in vitro to the ileal receptor and IF, but most of Ca++ could be removed with sialidase. The receptor-substrate complex contained Ca ++ and carbohydrate. The purified receptor was shown to contain two main subunits. The Imerslund-Gräsbeck syndrome was discovered 1958-1960; it is caused by mutations in either of two genes, cubilin or amnionless, which form the multiligand receptor cubam. Testicular biopsies during and after B 12-treated deficiency showed remarkable improvement after therapy. Studies of the turnover of radioactive B12 revealed biliary and fecal excretion, enterohepatic circulation and allowed calculation of biological half-life and daily need. The B12 coenzymes largely behaved like B12. To study whether radiocobalt in B12 was representative of the rest of the B12 molecule, 32P and 57Co labeled hydroxocobalamins were biosynthesized and shown to behave identically when given simultaneously to rats. The complex metabolism of B12 explains the pathogenesis of B12 deficiencies. Some of its mechanisms are not restricted to B12, e.g. the endocytosis of B12-IF also applies to other macromolecules. © 2013 Elsevier Masson SAS. All rights reserved.


Grasbeck R.,Minerva Foundation Institute for Medical Research | Tanner S.M.,Ohio State University
Pediatric Research | Year: 2011

Fifty years have passed since the description of juvenile selective malabsorption of cobalamin (Cbl). Quality of life improvements have dramatically reduced the incidence of parasite-induced or nutritional Cbl deficiency. Consequently, inherited defects have become a leading cause of Cbl deficiency in children, which is not always expressed as anemia. Unfortunately, the gold standard for clinical diagnosis, the Schilling test, has increasingly become unavailable, and replacement tests are only in their infancy. Genetic testing is complicated by genetic heterogeneity and differential diagnosis. This review documents the history, research, and advances in genetics that have elucidated the causes of juvenile Cbl malabsorption. Genetic research has unearthed many cases in the past decade, mostly in Europe and North America, often among immigrants from the Middle East or North Africa. Lack of suitable clinical testing potentially leaves many patients inadequately diagnosed. The consequences of suboptimal Cbl levels for neurological development are well documented. By raising awareness, we wish to push for fast track development of better clinical tools and suitable genetic testing. Clinical awareness must include attention to ethnicity, a sensitive topic but effective for fast diagnosis. The treatment with monthly parenteral Cbl for life offers a simple and cost-effective solution once proper diagnosis is made. Copyright © 2011 International Pediatric Research Foundation, Inc.


Weber-Boyvat M.,Minerva Foundation Institute for Medical Research | Zhong W.,Jinan University | Yan D.,Jinan University | Olkkonen V.M.,Minerva Foundation Institute for Medical Research | Olkkonen V.M.,University of Helsinki
Biochemical Pharmacology | Year: 2013

Oxysterol-binding (OSBP)-related proteins (ORPs) constitute a family of sterol and phosphoinositide binding/transfer proteins in eukaryotes from yeast to man. While their functions have mainly been addressed in cellular lipid metabolism or sterol transport, increasing evidence points to more versatile regulatory roles in a spectrum of cellular regimes. In fact ORPs do not appear to be robust controllers of lipid homeostasis. Several ORPs localize at membrane contacts sites (MCS), where endoplasmic reticulum (ER) is apposed with other organelle limiting membranes. Apparently, ORPs have the capacity to control the formation of MCS or activity of enzymatic machineries at these sites. Thereby, ORPs most likely affect organelle membrane lipid compositions, with impacts on signaling and vesicle transport, but also cellular lipid metabolism. Moreover, an increasing number of protein interaction partners of ORPs have been identified, connecting these proteins with various aspects of cell regulation. Small molecular anti-proliferative compounds, ORPphilins, were recently found to target two members of the ORP family, OSBP and ORP4, revealing an essential function of ORPs in cancer cell proliferation and survival. Further functions assigned for ORPs include regulation of extracellular signal regulated kinase (ERK) activity (OSBP), control of ER-late endosome MCS and late endosome motility (ORP1L), regulation of b1-integrin activity (ORP3), modulation of hepatocyte insulin signaling and macrophage migration (ORP8), as well as post-Golgi vesicle transport, phosphatidylinositol-4-phosphate and target of rapamycin complex 1 signaling and nitrogen sensing (Saccharomyces cerevisiae Osh4p). These and other recent observations shed light on the ORPs as integrators of lipid signals with an unforeseen variety of vital cellular processes. © 2013 Elsevier Inc. All rights reserved.


Yki-Jarvinen H.,University of Helsinki | Yki-Jarvinen H.,Minerva Foundation Institute for Medical Research
The Lancet Diabetes and Endocrinology | Year: 2014

Metabolic syndrome is a cluster of metabolic abnormalities that identifies people at risk of diabetes and cardiovascular disease, whereas non-alcoholic fatty liver disease (NAFLD) is defined as a disorder with excess fat in the liver due to non-alcoholic causes. Two key components of metabolic syndrome, glucose and triglycerides, are overproduced by the fatty liver. The liver is therefore a key determinant of metabolic abnormalities. The prevalence of both metabolic syndrome and NAFLD increases with obesity. Other acquired causes for both disorders include excessive intake of simple sugars and physical inactivity. Both disorders predict type 2 diabetes, cardiovascular disease, non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma. Because metabolic syndrome can be defined in many different ways, NAFLD might be a more direct predictor of these diseases. Half of people with NAFLD carry at least one variant (G) allele at rs738409 in the PNPLA3 gene, which is associated with high liver fat content. Steatosis in PNPLA3-associated NAFLD is not accompanied by features of metabolic syndrome. All forms of NAFLD increase the risk of NASH, cirrhosis, and hepatocellular carcinoma. © 2014 Elsevier Ltd.

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