ATP-Binding Cassette Transporter A1 Deficiency in Human Induced Pluripotent Stem Cell-Derived Hepatocytes Abrogates HDL Biogenesis and Enhances Triglyceride.

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ATP-Binding Cassette Transporter A1 Deficiency in Human Induced Pluripotent Stem Cell-Derived Hepatocytes Abrogates HDL Biogenesis and Enhances Triglyceride Secretion Xin Bi, Evanthia E. Pashos, Marina Cuchel, Nicholas N. Lyssenko, Mayda Hernandez, Antonino Picataggi, James McParland, Wenli Yang, Ying Liu, Ruilan Yan, Christopher Yu, Stephanie L. DerOhannessian, Michael C. Phillips, Edward E. Morrisey, Stephen A. Duncan, Daniel J. Rader EBioMedicine Volume 18, Pages 139-145 (April 2017) DOI: 10.1016/j.ebiom.2017.03.018 Copyright © 2017 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Terms and Conditions

Fig. 1 Impaired cholesterol efflux in TD HLCs. (A) Cholesterol efflux in the absence of exogenous apoA-I was compared between control-1 and TD-1 HLCs. All samples from the 3 clones of each group were compared. n=9, * denotes p<0.05. (B) Cholesterol efflux without (white bar) or with (black bar) addition of exogenous apoA-I (20μg/ml) was compared for each group. n=3, * denotes p<0.05. Values are shown as mean±SEM. EBioMedicine 2017 18, 139-145DOI: (10.1016/j.ebiom.2017.03.018) Copyright © 2017 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Terms and Conditions

Fig. 2 Lack of nascent HDL formation in TD HLCs. (A and B) Gel-filtration chromatography profiles of nascent HDL formed in the absence of exogenous apoA-I based on 3H-choline-PL (A) and 14C-cholesterol (B) counts. (C and D) Gel-filtration chromatography profiles of nascent HDL formed in the presence of 20μg/ml exogenous apoA-I based on 3H-choline-PL (C) and 14C-cholesterol (D) counts across fractions. EBioMedicine 2017 18, 139-145DOI: (10.1016/j.ebiom.2017.03.018) Copyright © 2017 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Terms and Conditions

Fig. 3 Elevated TG secretion in TD vs. control HLCs. (A) Newly synthesized TG that was secreted into medium. Medium 3H-TG counts were normalized to media albumin mass. Data is presented as cpm 3H-TG/μg secreted albumin. (B) Percent of newly synthesized TG secretion. The percentage of TG secretion was calculated by dividing 3H-TG in the medium by the sum of counts in the medium and cells and multiplying by 100. All samples from the 3 clones of each group were compared. Values are shown as mean±SEM. n=8–9, * denotes p<0.05. EBioMedicine 2017 18, 139-145DOI: (10.1016/j.ebiom.2017.03.018) Copyright © 2017 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Terms and Conditions

Fig. 4 Transcriptome profiles of HLCs and validation of ANGPTL3. (A) The overlap of genes expressed in TD-1 and control-1 HLCs was evaluated by Pearson Correlation Coefficient. (B) Heat map of pluripotency and hepatic markers between groups. (C) Heat map of differentially expressed lipid-related genes according to Gene Ontology lipid terms. (D) Expression of ANGPTL3 measured by RT-PCR. (E) Culture medium ANGPTL3 protein concentrations determined by ELISA. (F) Plasma ANGPTL3 levels were measured by ELISA. Values are shown as mean±SEM. n=9 for RT-PCR analysis. n=3 for culture medium ELISA. n=4–19 for plasma ANGPTL3 ELISA. * denotes p<0.05. EBioMedicine 2017 18, 139-145DOI: (10.1016/j.ebiom.2017.03.018) Copyright © 2017 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Terms and Conditions