Recapitulating lipid accumulation and related metabolic dysregulation in human liver-derived organoids

Ling Wang, Meng Li, Bingting Yu, Shaojun Shi, Jiaye Liu, Ruyi Zhang, Ibrahim Ayada, Monique M.A. Verstegen, Luc J.W. van der Laan, Maikel P. Peppelenbosch, Wanlu Cao, Qiuwei Pan*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Scopus)
279 Downloads (Pure)

Abstract

Fatty liver disease has grown into a major global health burden, attributed to multi-factors including sedentary lifestyle, obesogenic diet and prevalence of metabolic disorders. The lack of robust experimental models is hampering the research and therapeutic development for fatty liver disease. This study aims to develop an organoid-based 3D culture model to recapitulate key features of fatty liver disease focusing on intracellular lipid accumulation and metabolic dysregulation. We used human liver-derived intrahepatic cholangiocyte organoids and hepatocyte differentiated organoids. These organoids were exposed to lactate, pyruvate, and octanoic acid (LPO) for inducing lipid accumulation and mitochondrial impairment. Lipid accumulation resulted in alternations of gene transcription with major effects on metabolic pathways, including triglyceride and glucose level increase, which is consistent with metabolic changes in fatty liver disease patients. Interestingly, lipid accumulation affected mitochondria as shown by morphological transitions, alternations in expression of mitochondrial encoded genes, and reduction of ATP production. Meanwhile, we found treatment with obeticholic acid and metformin can alleviate fat accumulation in organoids. This study demonstrated that LPO exposure can induce lipid accumulation and associated metabolic dysregulation in human liver-derived organoids. This provides an innovative model for studying fatty liver disease and testing potential therapeutics. Key messages: Lactate, pyruvate, and octanoic acid induce lipid accumulation in liver organoids.Organoids of human compared to mouse origin are more efficient in lipid accumulation.Lipid accumulation dysregulates metabolic pathway and impairs mitochondrial function.Demonstrating a proof-of-concept for testing medications in organoids.

Original languageEnglish
Pages (from-to)471-484
Number of pages14
JournalJournal of Molecular Medicine
Volume100
Issue number3
Early online date20 Jan 2022
DOIs
Publication statusPublished - Mar 2022

Bibliographical note

Funding Information:
This research is supported by a VIDI grant (No. 91719300) from the Netherlands Organisation for Scientific Research (to Q. Pan), the Dutch Cancer Society for funding a Dutch Cancer Society Young Investigator Grant (10140) to Q. Pan, and China Scholarship Council for funding PhD fellowships to L. Wang (No.201708530248), S. Shi (No.201706230252) and R. Zhang (No.201808530490).

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

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