Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis.
Niemann-Pick C1 Like 1 (NPC1L1) is a protein localized in jejunal enterocytes that is critical for intestinal cholesterol absorption. The uptake of intestinal phytosterols and cholesterol into absorptive enterocytes in the intestine is not fully defined on a molecular level, and the role of NPC1L1 in maintaining whole body cholesterol homeostasis is not known. NPC1L1 null mice had substantially reduced intestinal uptake of cholesterol and sitosterol, with dramatically reduced plasma phytosterol levels. The NPC1L1 null mice were completely resistant to diet-induced hypercholesterolemia, with plasma lipoprotein and hepatic cholesterol profiles similar to those of wild type mice treated with the cholesterol absorption inhibitor ezetimibe. Cholesterol/cholate feeding resulted in down-regulation of intestinal NPC1L1 mRNA expression in wild type mice. NPC1L1 deficiency resulted in up-regulation of intestinal hydroxymethylglutaryl-CoA synthase mRNA and an increase in intestinal cholesterol synthesis, down-regulation of ABCA1 mRNA, and no change in ABCG5 and ABCG8 mRNA expression. NPC1L1 is required for intestinal uptake of both cholesterol and phytosterols and plays a major role in cholesterol homeostasis. Thus, NPC1L1 may be a useful drug target for the treatment of hypercholesterolemia and sitosterolemia.
Davis
Harry R
HR
Department of Cardiovascular/Metabolic Disease and Department of Discovery Technologies, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. harry.davis@spcorp.com
Zhu
Li-Ji
LJ
Hoos
Lizbeth M
LM
Tetzloff
Glen
G
Maguire
Maureen
M
Liu
Jianjun
J
Yao
Xiaorui
X
Iyer
Sai Prasad N
SP
Lam
My-Hanh
MH
Lund
Erik G
EG
Detmers
Patricia A
PA
Graziano
Michael P
MP
Altmann
Scott W
SW
D000818:Animals; D001692:Biological Transport; D002784:Cholesterol / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D006706:Homeostasis / Q000502:physiology*; D006937:Hypercholesterolemia / Q000209:etiology / Q000628:therapy; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000737:chemistry; D026901:Membrane Transport Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010840:Phytosterols / Q000097:blood / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012855:Sitosterols / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D002791:Cholesterol, Dietary; D008074:Lipoproteins; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D010840:Phytosterols; D012333:RNA, Messenger; D012855:Sitosterols; D014280:Triglycerides; C025473:gamma-sitosterol; D002784:Cholesterol