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

Abstract

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.

Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia

“…24 ABCA1 plays a key role in HDL production by mediating the formation of nascent HDL via ABCA1dependent lipidation of lipid-poor apoA-I that has just been produced. 37 Pemafibrate enhanced ABCA1 mRNA expression in the liver and small intestine of LDL receptor knockout mice 38 and primary human hepatocytes. 39 Smaller HDL species play major roles in cholesterol efflux from macrophages via ABCA1 and ABCG1.…”

The Use of Human Pluripotent Stem Cells for Modeling Liver Development and Disease

“…Angiopoietin-related protein 3 has been associated with increased plasma triglyceride concentration and therefore may contribute to the hypertriglyceridemia observed in Tangier disease. (39) As such, this study was able to identify a new target for small-compound development, which could alleviate some of the etiology associated with Tangier disease.…”

“…Tangier disease is another example of modeling and mechanistically investigating a disease process using hepatocyte-like cells, resulting in a clinically significant finding. (39) Tangier disease is caused by mutations in the adenosine triphosphate-binding cassette transporter A1 gene, manifesting in reduced high-density lipoprotein and increased triglyceride plasma concentrations. Transcriptomic analysis of hepatocytes derived from Tangier disease iPSCs identified significantly increased expression of angiopoietin-related protein 3 compared to controls.…”

The NextGen Genetic Association Studies Consortium: A Foray into In Vitro Population Genetics

“…One study used a familial hypercholesterolemia cohort to perform a ''trial in a dish,'' screening the effect of chemical compounds on hepatic LDL uptake (Cayo et al, 2017). Two other studies discovered novel underlying mechanisms of Tangier disease (Bi et al, 2017) and familial pulmonary arterial hypertension (Gu et al, 2017) using transcriptomics and genome editing. We expect that the ''trial-in-a-dish,'' molecular profiling, and genome editing methodologies employed in these manuscripts will be attractive strategies for studying common diseases with iPSCs.…”