title: Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis.
abstract: 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.
authors.affiliation: Department of Cardiovascular/Metabolic Disease and Department of Discovery Technologies, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. harry.davis@spcorp.com
authors.forename: Harry R
authors.initials: HR
authors.lastname: Davis
authors.forename: Li-Ji
authors.initials: LJ
authors.lastname: Zhu
authors.forename: Lizbeth M
authors.initials: LM
authors.lastname: Hoos
authors.forename: Glen
authors.initials: G
authors.lastname: Tetzloff
authors.forename: Maureen
authors.initials: M
authors.lastname: Maguire
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.forename: Xiaorui
authors.initials: X
authors.lastname: Yao
authors.forename: Sai Prasad N
authors.initials: SP
authors.lastname: Iyer
authors.forename: My-Hanh
authors.initials: MH
authors.lastname: Lam
authors.forename: Erik G
authors.initials: EG
authors.lastname: Lund
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Detmers
authors.forename: Michael P
authors.initials: MP
authors.lastname: Graziano
authors.forename: Scott W
authors.initials: SW
authors.lastname: Altmann
mesh_terms: 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
chemical_list: 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