Cholesterol Signaling at the Endoplasmic Reticulum Occurs in npc 1 but Not in npc 1, LDLR Mice

It remains controversial whether deficiency of the Niemann[n- ]Pick C1 (npc1) protein results in altered cholesterol signaling at the endoplasmic reticulum (ER). In this report, we have measured the processed, nuclear form of sterol regulatory element binding protein (SREBP)-1 in livers of npc1 wild-type, heterozygous, and homozygous deficient mice, alone, and in combination with deficiencies of the low density lipoprotein receptor (LDLR) or the multiple drug resistant (mdr)1a, P-glycoprotein. Cleavage of SREBPs to activated forms normally occurs when the ER is deficient in cholesterol. A large decrease in processed SREBP-1 was evident in fasted npc1 super(-) mice and npc1 super(-), mdr1a super(-) mice, with no decrease evident in npc1 super(-), LDLR super(-) mice. These results suggest that the increase in cellular cholesterol which occurs in npc1 super(-) and in npc1 super(-), mdr1a super(-) mice includes the sites responsible for cholesterol signaling, while the similar increase in cholesterol found in npc1 super(-), LDLR super(-) mice does not. Copyright 2001 Academic Press.