NPC1-like intracellular cholesterol transporter 1

Function

Plays a major role in cholesterol homeostasis. Critical for the uptake of cholesterol across the plasma membrane of the intestinal enterocyte. Involved in plant sterol absorption, it transports sitosterol, although at lower rates than cholesterol (By similarity). Is the direct molecular target of ezetimibe, a drug that inhibits cholesterol absorption and is approved for the treatment of hypercholesterolemia. May have a function in the transport of multiple lipids and their homeostasis, thereby influencing lipid metabolism regulation. May be involved in caveolin trafficking from the plasma membrane (By similarity). In addition, acts as a negative regulator of NPC2 and down-regulates its expression and secretion by inhibiting its maturation and accelerating its degradation.

Classification

Family (Pfam)

PF22314 NPC1_MLD, PF16414 NPC1_N, PF12349 Sterol-sensing

InterPro

HMGCR/SNAP/NPC1-like_SSD, NPC1_MLD, NPC1_N, SSD

Functional cluster

Secreted Growth Factors & Cytokines

Experimental structures · PDB · 7

• 3QNT X-ray 2.83A
• 7DF8 EM 3.03A
• 7DFW EM 2.69A
• 7DFZ EM 3.58A
• 7N4U EM 3.34A
• 7N4V EM 3.58A
• 7N4X EM 3.33A

A predicted model is available from AlphaFold.

Gene Ontology · 17

• GO:0016324 apical plasma membrane
• GO:0030659 cytoplasmic vesicle membrane
• GO:0005886 plasma membrane
• GO:0015485 cholesterol binding
• GO:0031489 myosin V binding
• GO:0042803 protein homodimerization activity
• GO:0031267 small GTPase binding
• GO:0008431 vitamin E binding
• GO:0071501 cellular response to sterol depletion
• GO:0006695 cholesterol biosynthetic process
• GO:0042632 cholesterol homeostasis
• GO:0030301 cholesterol transport
• GO:0030299 intestinal cholesterol absorption
• GO:0042157 lipoprotein metabolic process
• GO:0015918 sterol transport
• GO:0042360 vitamin E metabolic process
• GO:0051180 vitamin transport

Disease associations

• OMIM:617966 RAW:OMIM_617966

Drugs targeting this protein · 1

• EZETIMIBE inhibitor

Related proteins · sequence + function similarity

• NPC1-like intracellular cholesterol transporter 1 0.95
• NPC1-like intracellular cholesterol transporter 1 0.95
• NPC intracellular cholesterol transporter 1 0.75
• NPC intracellular cholesterol transporter 1 0.74
• NPC intracellular cholesterol transporter 1 0.73
• Protein dispatched homolog 2 0.69
• Protein patched homolog 2 0.69
• Protein patched homolog 2 0.69
• Protein dispatched homolog 2 0.68
• ATP-binding cassette sub-family A member 7 0.65
• ATP-binding cassette sub-family A member 7 0.65
• Protein dispatched homolog 3 0.64

Co-cited proteins · studied together in the literature

• NPC1-like intracellular cholesterol transporter 1 4 shared papers
• NPC1-like intracellular cholesterol transporter 1 3 shared papers
• NPC intracellular cholesterol transporter 2 1 shared papers
• Peroxisome proliferator-activated receptor delta 1 shared papers
• Unconventional myosin-Vb 2 shared papers
• LIM domain and actin-binding protein 1 1 shared papers
• Unconventional myosin-Vb 1 shared papers
• Rab11 family-interacting protein 2 1 shared papers
• LIM domain and actin-binding protein 1 1 shared papers
• Ras-related protein Rab-11A 1 shared papers

Literature · 15 cited papers

• A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption. Science · 2018
• Inactivating mutations in NPC1L1 and protection from coronary heart disease. N. Engl. J. Med. · 2014
• Novel function of Niemann-Pick C1-like 1 as a negative regulator of Niemann-Pick C2 protein. Hepatology · 2012
• The structure of the NPC1L1 N-terminal domain in a closed conformation. PLoS ONE · 2011
• Requirement of myosin Vb.Rab11a.Rab11-FIP2 complex in cholesterol-regulated translocation of NPC1L1 to the cell surface. J. Biol. Chem. · 2009
• Membrane topology of human NPC1L1, a key protein in enterohepatic cholesterol absorption. J. Lipid Res. · 2009
• The target of ezetimibe is Niemann-Pick C1-like 1 (NPC1L1). Proc. Natl. Acad. Sci. U.S.A. · 2005
• Compound heterozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe. Clin. Genet. · 2005
• Inactivation of NPC1L1 causes multiple lipid transport defects and protects against diet-induced hypercholesterolemia. J. Biol. Chem. · 2005
• Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestinal expression of NPC1L1. J. Lipid Res. · 2005
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol absorption. Science · 2004
• … and 3 more in the literature graph