Modeling Nonalcoholic Fatty Liver Disease with Human Pluripotent Stem Cell-Derived Immature Hepatocyte-Like Cells Reveals Activation of PLIN2 and Confirms Regulatory Functions of Peroxisome Proliferator-Activated Receptor Alpha.
Nonalcoholic fatty liver disease (NAFLD/steatosis) is a metabolic disease characterized by the incorporation of fat into hepatocytes. In this study, we developed an in vitro model for NAFLD based on hepatocyte-like cells (HLCs) differentiated from human pluripotent stem cells. We induced fat storage in these HLCs and detected major expression changes of metabolism-associated genes, as well as an overall reduction of liver-related microRNAs. We observed an upregulation of the lipid droplet coating protein Perilipin 2 (PLIN2), as well as of numerous genes of the peroxisome proliferator-activated receptor (PPAR) pathway, which constitutes a regulatory hub for metabolic processes. Interference with PLIN2 and PPARα resulted in major alterations in gene expression, especially affecting lipid, glucose, and purine metabolism. Our model recapitulates many metabolic changes that are characteristic for NAFLD. It permits the dissection of disease-promoting molecular pathways and allows us to investigate the influences of distinct genetic backgrounds on disease progression.
1 Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf , Düsseldorf, Germany .
Nina
N
Graffmann
1 Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf , Düsseldorf, Germany .
Sarah
S
Ring
1 Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf , Düsseldorf, Germany .
Marie-Ann
MA
Kawala
1 Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf , Düsseldorf, Germany .
Wasco
W
Wruck
1 Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf , Düsseldorf, Germany .
Audrey
A
Ncube
2 Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University Düsseldorf , Düsseldorf, Germany .
Hans-Ingo
HI
Trompeter
1 Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf , Düsseldorf, Germany .
James
J
Adjaye
D002454:Cell Differentiation / Q000235:genetics; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D066292:Lipid Droplets / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009928:Organ Specificity / Q000235:genetics; D047493:PPAR alpha / Q000378:metabolism*; D000070780:Perilipin-2 / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics
D035683:MicroRNAs; D047493:PPAR alpha; D000070780:Perilipin-2; D034741:RNA, Small Interfering