Fatty Liver Disease and Diabetes
The main goal is to study the pathogenesis of fatty liver disease and diabetes in humans with a special focus on the role of hepatic mitochondrial metabolism.
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 variants in PNPLA3, TM6SF2 and MBOAT7 only predispose to liver disease. We have recently shown that the the pathogenic mechanisms underlying the metabolic and genetic components of NAFLD are fundamentally different. The metabolic component is characterized with substrate surplus and increased rates of adipose tissue lipolysis and hepatic de novo lipogenesis (DNL). In contrast, the genetic component is not and is instead characterized by increased hepatic mitochondrial redox state, a marker of mitochondrial dysfunction.
Very recently, we demonstrated that the PNPLA3 variant paradoxically decreases hepatic DNL, which was associated with a decreased rate of hepatic mitochondrial citrate synthase flux, i.e. the rate-limiting step of the TCA cycle which also provides citrate for DNL. In contrast, ketogenesis was increased since the acetyl CoA formed during oxidation of fatty acids was unable to enter the TCA cycle. Together, these data show that the PNPLA3 variant, which is the strongest genetic risk factor of NAFLD, induces hepatic mitochondrial dysfunction. These findings have implications in the treatment of NAFLD. Inhibitors of DNL might be harmful in PNPLA3 variant carriers, while pharmacotherapies that stimulate hepatic mitochondrial function, such as thyroid hormone receptor agonists or mitochondrial uncouplers could be a logical treatment option for these patients.
We perform human clinical studies combining novel stable isotope methods, metabolomics and genetics to investigate the pathogenesis of fatty liver disease and diabetes. In addition, we use a vertical research approach by combining analyses of large-scale datasets to validate our hypotheses at the population level with mouse and in vitro experiments to elucidate the underlying molecular mechanisms.
Selected publications
Luukkonen PK, Porthan K, Ahlholm N, Rosqvist F, Dufour S, Zhang XM, Lehtimäki TE, Seppänen W, Orho-Melander M, Hodson L, Petersen KF, Shulman GI, Yki-Järvinen H. The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans. Cell Metab. 2023:S1550-4131(23)00377-7.
Luukkonen PK, Sakuma I, Gaspar RC, Mooring M, Nasiri A, Kahn M, Zhang XM, Zhang D, Sammalkorpi H, Penttilä AK, Orho-Melander M, Arola J, Juuti A, Zhang X, Yimlamai D, Yki-Järvinen H, Petersen KF, Shulman GI. Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis. Proc Natl Acad Sci U S A. 2023;120(4):e2217543120.
Tamaki N*, Ahlholm N*, Luukkonen PK, Porthan K, Sharpton SR, Ajmera V, Kono Y, Dave S, Ahmed A, Sundaram V, Wilkinson MJ, Patton H, Gupta H, Cervantes V, Hernandez C, Lopez SJ, Loomba R, Baumgartner A, Richards L, Arkkila PE, Nemes K, Isoniemi H, Yki-Järvinen H, Loomba R. Risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease. J Clin Invest. 2022;132(21):e162513.
Luukkonen PK, Qadri S, Ahlholm N, Porthan K, Männistö V, Sammalkorpi H, Penttilä AK, Hakkarainen A, Lehtimäki TE, Gaggini M, Gastaldelli A, Ala-Korpela M, Orho-Melander M, Arola J, Juuti A, Pihlajamäki J, Hodson L, Yki-Järvinen H. Distinct Contributions of Metabolic Dysfunction and Genetic Risk Factors in the Pathogenesis of Non-Alcoholic Fatty Liver Disease. J Hepatol. 2022;76(3):526-535.
Yki-Järvinen H, Luukkonen PK, Hodson L, Moore JB. Dietary carbohydrates and fats in NAFLD. Nat Rev Gastroenterol Hepatol. 2021;18(11):770-786.
Luukkonen PK, Dufour S, Lyu K, Zhang XM, Hakkarainen A, Lehtimäki TE, Cline GW, Petersen KF, Shulman GI*, Yki-Järvinen H*. Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A. 2020;117(13):7347-7354.
Luukkonen PK, Tukiainen T, Juuti A, Sammalkorpi H, Nidhina Haridas PA, Niemelä O, Arola J, Orho-Melander M, Hakkarainen A, Kovanen PT, Dwivedi O, Groop L, Hodson L, Gastaldelli A, Hyötyläinen T, Oresic M, Yki-Järvinen H. Hydroxysteroid 17-β dehydrogenase increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease. JCI Insight. 2020;5(5).
Luukkonen PK*, Nick A*, Hölttä-Vuori M, Thiele C, Isokuortti E, Lallukka-Brück S, Zhou Y, Hakkarainen A, Lundbom N, Peltonen M, Orho-Melander M, Orešič M, Hyötyläinen T, Hodson L, Ikonen E, Yki-Järvinen H. Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids. JCI Insight. 2019;4(16):e127902.
Luukkonen PK, Sädevirta S, Zhou Y, Kayser B, Ali A, Ahonen L, Lallukka S, Pelloux V,Gaggini M, Jian C, Hakkarainen A, Lundbom N, Gylling H, Salonen A, Orešič M, Hyötyläinen T, Orho-Melander M, Rissanen A, Gastaldelli A, Clément K, Hodson L, Yki-Järvinen H. Saturated Fat is More Metabolically Harmful for the Human Liver than Unsaturated Fat or Simple Sugars. Diabetes Care. 2018;41(8):1732-1739.
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.
External funding
Academy of Finland
Emil Aaltonen Foundation
EU Horizon 2020, Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS)
Finnish Government Research Funding
Finnish Medical Foundation
Instrumentarium Science Foundation
Novo Nordisk Foundation
Orion Research Foundation
Sigrid Jusélius Foundation
University of Helsinki