LAUSR

Patients with genetic mutation of ATP-binding Cassette Transporter A1 (ABCA1), commonly known as Tangier Disease (TD), can be characterized by elevated levels of plasma triglycerides (hypertriglyceridemia) and low plasma high-density lipoprotein (HDL) levels. With current HDL therapies continuously failing in clinical trials, there is no cure for TD other than maintaining a very low fat diet. The lipid phenotype in TD is largely contributed by the defect in ABCA1 in the liver. Our understanding of human hepatic ABCA1 expression being crucial in the maturation towards HDL is largely characterized in healthy conditions. However, the direct defect incited by ABCA1 loss of function (LOF) mutations in hepatocytes in TD has never thoroughly been explored, as availability of human TD liver tissue for research is extremely scarce. Nevertheless, mouse models mimicking TD (i.e. Abca1) or by specifically deleting hepatic ABCA1 have been used to gain insight into potential mechanism of altered lipid metabolism, although translational relevance to humans remains uncertain. The work presented in this issue of EBioMedicine by Bi et al. (2017–in this issue), provides a valuable and translatable model in studying hepatocyte-specific function and mechanisms of human TD generated from induced pluripotent stem cells (iPSCs). ABCA1 is the rate-limiting step for the biogenesis of HDL mediated through cholesterol efflux. Specific deletion of Abca1 in the mouse liver leads to an ~75% reduction in circulating HDL (Timmins et al., 2005), highlighting the crucial role of hepatic ABCA1 in maintaining plasma HDL levels. ABCA1 deficiency in hepatocytes also results in elevated levels of plasma triglycerides (TG). As discussed by Timmins et al., this can be via two mechanisms: 1) An overproduction of TGenriched VLDL particles in the liver (Shelness and Sellers, 2001) and 2) decreased TG clearance, due to reduced LPL activity. The factors that affect the overproduction of VLDL are complex and depend on the availability of lipid substrates and protein co-factors to load lipids into VLDL particles. VLDL biogenesis occurs when apolipoprotein B (apoB) becomes lipidated bymicrosomal triglyceride transfer protein in the endoplasmic reticulum before lipids are added to form VLDL2. When TG availability is high in the Golgi apparatus, VLDL2 can further undergo maturation into VLDL1 (TG-enriched) particles, which is thenmobilized into circulation. Generally, phosphoinositide 3-kinase (PI3K) acts as a