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A nonalcoholic fatty liver disease model in human induced pluripotent stem cell-derived hepatocytes, created by endoplasmic reticulum stress-induced steatosis
- Source :
- Disease Models & Mechanisms, Disease Models & Mechanisms, Vol 11, Iss 9 (2018)
- Publication Year :
- 2018
- Publisher :
- The Company of Biologists Ltd, 2018.
-
Abstract
- Hepatic steatosis, a reversible state of metabolic dysregulation, can promote the onset of nonalcoholic steatohepatitis (NASH), and its transition is thought to be critical in disease evolution. The association between endoplasmic reticulum (ER) stress response and hepatocyte metabolism disorders prompted us to characterize ER stress-induced hepatic metabolic dysfunction in human induced pluripotent stem cell-derived hepatocytes (hiPSC-Hep), to explore regulatory pathways and validate a phenotypic in vitro model for progression of liver steatosis. We treated hiPSC-Hep with a ratio of unsaturated and saturated fatty acids in the presence of an inducer of ER stress to synergistically promote triglyceride accumulation and dysregulate lipid metabolism. We monitored lipid accumulation by high-content imaging and measured gene regulation by RNA sequencing and reverse transcription quantitative PCR analyses. Our results show that ER stress potentiated intracellular lipid accumulation by 5-fold in hiPSC-Hep in the absence of apoptosis. Transcriptome pathway analysis identified ER stress pathways as the most significantly dysregulated of all pathways affected. Obeticholic acid dose dependently inhibited lipid accumulation and modulated gene expression downstream of the farnesoid X receptor. We were able to identify modulation of hepatic markers and gene pathways known to be involved in steatosis and nonalcoholic fatty liver disease (NAFLD), in support of a hiPSC-Hep disease model that is relevant to clinical data for human NASH. Our results show that the model can serve as a translational discovery platform for the understanding of molecular pathways involved in NAFLD, and can facilitate the identification of novel therapeutic molecules based on high-throughput screening strategies.<br />Summary: Our study demonstrates expanded use of human induced pluripotent stem cell-derived hepatocytes for molecular studies and drug screening, to evaluate new therapeutics with an antisteatotic mechanism of action for nonalcoholic fatty liver disease.
- Subjects :
- 0301 basic medicine
Time Factors
Medicine (miscellaneous)
lcsh:Medicine
Receptors, Cytoplasmic and Nuclear
Lipid accumulation
Immunology and Microbiology (miscellaneous)
Non-alcoholic Fatty Liver Disease
Nonalcoholic fatty liver disease
Cells, Cultured
Chemistry
Fatty Acids
RNA sequencing
Endoplasmic Reticulum Stress
3. Good health
Metabolism disorder
Cell biology
Up-Regulation
Phenotypic high-content analysis
medicine.anatomical_structure
Phenotype
Hepatocyte
Thapsigargin
ER stress
lcsh:RB1-214
Research Article
Induced Pluripotent Stem Cells
Neuroscience (miscellaneous)
Chenodeoxycholic Acid
Models, Biological
General Biochemistry, Genetics and Molecular Biology
NAFLD in vitro model
03 medical and health sciences
medicine
lcsh:Pathology
Humans
Cell Shape
Triglycerides
Endoplasmic reticulum
Lipogenesis
lcsh:R
Lipid metabolism
medicine.disease
Dd
030104 developmental biology
Gene Ontology
Gene Expression Regulation
Unfolded protein response
Hepatocytes
Unfolded Protein Response
Induced pluripotent stem cell-derived hepatocytes
Farnesoid X receptor
Steatosis
Transcriptome
Subjects
Details
- Language :
- English
- ISSN :
- 17548411 and 17548403
- Volume :
- 11
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Disease Models & Mechanisms
- Accession number :
- edsair.doi.dedup.....c9eab5f9e918b4601d9d3623fcb7822b