ATP-Binding Cassette Transporter A1 Deficiency in Human Induced Pluripotent Stem Cell-Derived Hepatocytes Abrogates HDL Biogenesis and Enhances Triglyceride Secretion.
Despite the recognized role of the ATP-binding Cassette Transporter A1 (ABCA1) in high-density lipoprotein (HDL) metabolism, our understanding of ABCA1 deficiency in human hepatocytes is limited. To define the functional effects of human hepatocyte ABCA1 deficiency, we generated induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (HLCs) from Tangier disease (TD) and matched control subjects. Control HLCs exhibited robust cholesterol efflux to apolipoprotein A-I (apoA-I) and formed nascent HDL particles. ABCA1-deficient HLCs failed to mediate lipid efflux or nascent HDL formation, but had elevated triglyceride (TG) secretion. Global transcriptome analysis revealed significantly increased ANGPTL3 expression in ABCA1-deficient HLCs. Angiopoietin-related protein 3 (ANGPTL3) was enriched in plasma of TD relative to control subjects. These results highlight the required role of ABCA1 in cholesterol efflux and nascent HDL formation by hepatocytes. Furthermore, our results suggest that hepatic ABCA1 deficiency results in increased hepatic TG and ANGPTL3 secretion, potentially underlying the elevated plasma TG levels in TD patients.
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Xin
X
Bi
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Evanthia E
EE
Pashos
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Marina
M
Cuchel
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Nicholas N
NN
Lyssenko
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Mayda
M
Hernandez
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Antonino
A
Picataggi
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
James
J
McParland
Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Wenli
W
Yang
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Ying
Y
Liu
Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Ruilan
R
Yan
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Christopher
C
Yu
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Stephanie L
SL
DerOhannessian
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Michael C
MC
Phillips
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Edward E
EE
Morrisey
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, SC 29425, USA.
Stephen A
SA
Duncan
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania and Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: rader@mail.med.upenn.edu.
Daniel J
DJ
Rader
D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism*; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D008075:Lipoproteins, HDL / Q000378:metabolism*; D013631:Tangier Disease / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome; D014280:Triglycerides / Q000378:metabolism
C577836:ABCA1 protein, human; C479896:ANGPTL3 protein, human; D064286:ATP Binding Cassette Transporter 1; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D014280:Triglycerides; D002784:Cholesterol
HDL biogenesis; Induced pluripotent stem cells; Tangier disease; Triglyceride secretion; iPSC-derived hepatocytes