Mapping proteome and lipidome changes in early-onset non-alcoholic fatty liver disease using hepatic 3D spheroids

Helle Sedighi Frandsen, Joel Mario Vej-Nielsen, Lauren Elizabeth Smith, Lang Sun, Karoline Lindgaard Mikkelsen, Annemette Præstegaard Thulesen, Christina Erika Hagensen, Fuquan Yang, Adelina Rogowska-Wrzesinska*

*Kontaktforfatter

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Abstract

Non-alcoholic fatty liver disease affects one-fourth of the world’s population. Central to the disease progression is lipid accumulation in the liver, followed by inflammation, fibrosis and cirrhosis. The underlying mechanism behind the early stages of the disease is poorly understood. We have exposed human hepatic HepG2/C3A cells-based spheroids to 65 μM oleic acid and 45 μM palmitic acid and employed proteomics and lipidomics analysis to investigate their effect on hepatocytes. The treatment successfully induced in vivo hallmarks of NAFLD, as evidenced by intracellular lipid accumulation and increased ATP levels. Quantitative lipidome analysis revealed an increase in ceramides, LPC and saturated triglycerides and a decrease in the ratio of PC/PE, similar to the changes observed in patients’ liver biopsies. The proteomics analysis combined with qPCR showed increased epithelial to mesenchymal transition (EMT) signalling. Activation of EMT was further validated by transcriptomics in TGF-β treated spheroids, where an increase in mesenchymal cell markers (N-cadherin and collagen expression) was found. Our study demonstrates that this model system thus closely echoes several of the clinical features of non-alcoholic fatty liver disease and can be used to investigate the underlying molecular changes occurring in the condition.

OriginalsprogEngelsk
Artikelnummer3216
TidsskriftCells
Vol/bind11
Udgave nummer20
ISSN2073-4409
DOI
StatusUdgivet - okt. 2022

Bibliografisk note

Funding Information:
The authors acknowledge the financial support from the Sino Danish Research and Education Center for Ph.D. projects for HSF and JMVN; The Danish National Research Foundation for the LES postdoc project from January 2019 to July 2020. The liquid chromatography and mass spectrometry instrumentation are part of the VILLUM Center for Bioanalytical Sciences at SDU supported by the VILLUM Foundation, and PRO-MS research infrastructure is supported by a generous grant from the Danish Ministry of Higher Education and Science.

Publisher Copyright:
© 2022 by the authors.

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