Cholesterol signaling at the endoplasmic reticulum occurs in npc1(-/-) butnot in npc1(-/-), LDLR-/- mice

It remains controversial whether deficiency of the Niemann-Pick C1 (npc1) p rotein results in altered cholesterol signaling at the endoplasmic reticulu m (ER). In this report, we have measured the processed, nuclear form of ste rol regulatory element binding protein (SREBP)-1 in livers of npc1 wild-typ e, heterozygous, and homozygous deficient mice, alone, and in combination w ith deficiencies of the low density lipoprotein receptor (LDLR) or the mult iple drug resistant (mdr)1a, P-glycoprotein. Cleavage of SREBPs to activate d forms normally occurs when the ER is deficient in cholesterol. A large de crease in processed SREBP-1 was evident in fasted npc1(-/-) mice and npc1(- /-), mdr1a(-/-) mice, with no decrease evident in npc1(-/-), LDLR-/- mice. These results suggest that the increase in cellular cholesterol which occur s in npc1(-/-) and in npc1(-/-), mdr1a(-/-) mice includes the sites respons ible for cholesterol signaling, while the similar increase in cholesterol f ound in npc1(-/-), LDLR-/- mice does not. (C) 2001 Academic Press.