CELLULAR NEUROCIENCE | NEURONAL SIGNALING | CARDIOVASCULAR RESEARCH | METABOLISM | LIPID SIGNALING AND HOMEOSTASIS | ENDOCRINOLOGY | CELLULAR PHYSIOLOGY | TARGETED GENE-EXPRESSION ANALYSIS | MEMBRANE BIOLOGY | TELOMERE RESEARCH
Hannele Yki-Järvinen, M.D., F.R.C.P, Professor, Head
Panu Luukkonen, M.D.
Sanja Sädevirta, M.D.
Nidhina Haridas, Ph.D.
Susanna Lallukka, M.D.
Elina Isokuortti, M.D.
Jenni Hyysalo, M.D.
Laura Ahtiainen, medical student
Mari Lahelma, medical student
Iida Tuokkola, medical student
Markus Kallio, medical student
Sanja Sädevirta, M.D.
Antti Hakkarainen, M.Sc. Techn.
You Zhou, Ph.D. (bioinformatics analyses)
Aila Karioja-Kallio, laboratory technician, research nurse
Päivi Ihamuotila, laboratory technician, research nurse
Non-alcoholic fatty liver disease (NAFLD) is heterogenous. 'Metabolic' NAFLD predicts both advanced liver and metabolic (type 2 diabetes) disease, while common genetic forms attributable to 3 distinct genetic variants in PNPLA3, TM6SF2 and MBOAT7 only predispose to liver disease. We have recently shown that the liver lipidome differs markedly between the different forms. We now wish to use stable isotope approaches, RNA sequencing of human liver samples, label free imaging of liver slices in vitro, and magnetic resonance elastography (MRE) for noninvasive 3D quantification of liver fibrosis, to examine the pathogenesis of 5 different forms (‘Metabolic’, 3 different genetic forms, lipodystrophic) of NAFLD in humans.
- PNPLA3 I148M gene variant accelerates synthesis of liver polyunsaturated triglycerides (TGs) relative to saturated TAGs in ‘PNLA3 NAFLD’ compared to ‘Metabolic NAFLD’.
- Our in vivo and in vitro data suggest that the E167K gene variant increases liver TGs and cholesterol esters (CEs) by impairing synthesis of polyunsaturated phosphatidylcholines (PCs).
- MBOAT7 deficiency decreases incorporation of 13C-labeled polyunsaturated fatty acids into phosphatidylinositols (PIs) from 13C–labeled 18:2 and 20:4 acylated fatty acids in VLDL-TAG.
- Distinct changes in gene expression as determined by RNA sequencing characterizes subtypes of NAFLD.
- Localization of steatosis, fibrosis and hypoxia in the liver is similar irrespective of the cause of NAFLD.
- Inflammation in adipose tissue in lipodystrophic NAFLD increases the flux of FFA to the liver. The hyperinsulinemia characterizing these patients is associated with increased DNL as in ‘Metabolic NAFLD’. Long-standing lipodystrophy leads to fibrosis in the liver which is similar to that observed in ‘Metabolic NAFLD’.
- EU projects EPoS (elucidating pathways of non-alcoholic steatohepatitis) and EMIF. We contribute to EPoS (dietary intervention study, sample collection, grant n° 634413, www.epos-nafld.eu) and EMIF (biomarker discovery, EMIF grant n° 115372, www.emif.eu).
The pathogenetic studies allow identification pathways of drug targets and help in understanding why different types of NAFLD need different follow-up. The MRE technique will replace liver biopsies for NAFLD-fibrosis within 2-3 years. After being set-up and validated, the technique is available to clinicians.
Hannele Yki-Järvinen, M.D., D.Med.Sci., F.R.C.P, Professor
Tel: +358 2941 25708
Yki-Järvinen H: Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol. 2014; 2:901-910.
Parks E, Yki-Järvinen H, Hawkins M. Out of the frying pan: dietary saturated fat influences nonalcoholic fatty liver disease. J Clin Invest. 2017; 127:454-456.
Luukkonen PK, Zhou Y, Sädevirta S, Leivonen M, Arola J, Orešič M, Hyötyläinen T, Yki-Järvinen H. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J Hepatol. 2016; 64:1167-75.
Zhou Y, Orešič M, Leivonen M, Gopalacharyulu P, Hyysalo J, Arola J, Verrijken A, Francque S, Van Gaal L, Hyötyläinen T, Yki-Järvinen H. Noninvasive detection of nonalcoholic steatohepatitis using clinical markers and circulating levels of lipids and metabolites. Clin Gastroenterol Hepatol. 2016; 14:1463-1472.
Luukkonen PK, Zhou Y, Hyötyläinen T, Leivonen M, Arola J, Orho-Melander M, Orešič M, Yki-Järvinen H. The MBOAT7 variant rs641738 alters hepatic phosphatidylinositols and increases severity of non-alcoholic fatty liver disease in humans. J Hepatol. 2016; 65:1263-1265.Luukkonen PK, Zhou Y, Nidhina Haridas PA, Dwivedi OP, Hyötyläinen T, Ali A, Juuti A, Leivonen M, Tukiainen T, Ahonen L, Scott E, Palmer JM, Arola J, Orho-Melander M, Vikman P, Anstee QM, Olkkonen VM, Orešič M, Groop L, Yki-Järvinen H. Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers with NAFLD. J Hepatol. 2017; 67:128-136.