The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids

Sebastian Prill, Andrea Caddeo, Guido Baselli, Oveis Jamialahmadi, Paola Dongiovanni, Raffaela Rametta, Kajsa P. Kanebratt, Arturo Pujia, Piero Pingitore, Rosellina Margherita Mancina, Daniel Lindén, Carl Whatling, Annika Janefeldt, Mikael Kozyra, Magnus Ingelman-Sundberg, Luca Valenti, Tommy B. Andersson, Stefano Romeo

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Abstract

There is a high unmet need for developing treatments for nonalcoholic fatty liver disease (NAFLD), for which there are no approved drugs today. Here, we used a human in vitro disease model to understand mechanisms linked to genetic risk variants associated with NAFLD. The model is based on 3D spheroids from primary human hepatocytes from five different donors. Across these donors, we observed highly reproducible differences in the extent of steatosis induction, demonstrating that inter-donor variability is reflected in the in vitro model. Importantly, our data indicates that the genetic variant TM6SF2 E167K, previously associated with increased risk for NAFLD, induces increased hepatocyte fat content by reducing APOB particle secretion. Finally, differences in gene expression pathways involved in cholesterol, fatty acid and glucose metabolism between wild type and TM6SF2 E167K mutation carriers (N = 125) were confirmed in the in vitro model. Our data suggest that the 3D in vitro spheroids can be used to investigate the mechanisms underlying the association of human genetic variants associated with NAFLD. This model may also be suitable to discover new treatments against NAFLD.

Original languageEnglish
Article number11585
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

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    Prill, S., Caddeo, A., Baselli, G., Jamialahmadi, O., Dongiovanni, P., Rametta, R., Kanebratt, K. P., Pujia, A., Pingitore, P., Mancina, R. M., Lindén, D., Whatling, C., Janefeldt, A., Kozyra, M., Ingelman-Sundberg, M., Valenti, L., Andersson, T. B., & Romeo, S. (2019). The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids. Scientific Reports, 9(1), [11585]. https://doi.org/10.1038/s41598-019-47737-w