ATP-binding cassette transporters G1 and G4 mediate cholesterol and desmosterol efflux to HDL and regulate sterol accumulation in the brain

Transporters in the ABCG family appear to be involved in the cellular excretion of cholesterol and other sterols in a cell- and tissue-specific fashion. Overexpression of ATP-binding cassette transporters G1 (Abcg1) and G4 (Abcg4) can promote cellular cholesterol efflux to high-density lipoprotein (HDL), but the in vivo functions of Abcg4 are poorly understood. We used mice with knockouts of Abcg1 or Abcg4 singly or together to further elucidate the function of these transporters. Abcg1 and Abcg4 are highly expressed in the brain and are found in both astrocytes and neurons. Whereas Abcg2(-/-) or Abcg4(-/-) mice showed essentially normal levels of brain sterols, in Abcg1(-/-)/Abcg4(-/-) mice, levels of several sterol intermediates in the cholesterol biosynthetic pathway, namely desmosterol, lathosterol, and lanosterol, as well as 27-OH cholesterol, were increased 2- to 3-fold. Overexpression of Abcg1 or Abcg4 promoted efflux of desmosterol and cholesterol from cells to HDL, and combined deficiency of these transporters led to defective efflux and accumulation of these sterols in primary astrocytes. Consistent with defective efflux and sterol accumulation, cholesterol biosynthesis was reduced in Abcg1(-/-)/Abcg4(-/-) astrocytes. The accumulation of desmosterol, a known liver-X receptor (LXR) activator, was associated with increased expression of LXR target genes, including ATP-binding cassette transporter Al, and increased apolipoprotein E secretion in Abcg1(-/-)/ Abcg4-/- astrocytes. Our findings provide the first in vivo demonstration of a role for Abcg4 in sterol efflux in the brain and show that Abcg1 and Abcg4 have overlapping functions in astrocytes, promoting efflux of cholesterol, desmosterol, and possibly other sterol biosynthetic intermediates to HDL.