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

Autor:	Oveis Jamialahmadi, Annika Janefeldt, Carl Whatling, Luca Valenti, Mikael Kozyra, Kajsa P. Kanebratt, Tommy B. Andersson, Arturo Pujia, Paola Dongiovanni, Andrea Caddeo, Rosellina Margherita Mancina, Sebastian Prill, Magnus Ingelman-Sundberg, Stefano Romeo, Raffaela Rametta, Daniel Lindén, Guido Baselli, Piero Pingitore
Jazyk:	angličtina
Rok vydání:	2019
Předmět:	0301 basic medicine medicine.medical_specialty Apolipoprotein B lcsh:Medicine medicine.disease_cause Article Target validation 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Lipid biosynthesis Internal medicine Nonalcoholic fatty liver disease medicine Humans Tissue engineering lcsh:Science Apolipoproteins B Mutation Multidisciplinary biology Cholesterol lcsh:R Wild type Membrane Proteins medicine.disease Lipids 3. Good health 030104 developmental biology Endocrinology chemistry biology.protein lcsh:Q Steatosis Medical genomics 030217 neurology & neurosurgery Non-alcoholic fatty liver disease TM6SF2
Zdroj:	Scientific Reports, Vol 9, Iss 1, Pp 1-12 (2019) Scientific Reports
ISSN:	2045-2322
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6953b6f68cdc7dba1a2498c7059111ea http://link.springer.com/article/10.1038/s41598-019-47737-w Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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