• INSIG1 plays an important role in the
SREBP-mediated regulation of
cholesterol biosynthesis: by binding to the
sterol-sensing domain of
SCAP (
SREBP
cleavage
activating
protein) it makes the SCAP/SREBP complex stay longer in the ER, thus prohibiting SCAP from carrying activated SREBP to the
golgi complex. This ultimately blocks SREBP from acting as a transcription factor for the SRE in the promoter region of the
HMG-CoA-reductase gene and results in a decreased expression of HMG-CoA-reductase. • INSIG1 also binds to the sterol-sensing domain of HMG-CoA-reductase, resulting in the enzyme's increased degradation. Both functions require the binding of INSIG1 protein via the same site. There are two other proteins whose sterol-binding sites show a great similarity to the ones of SCAP and HMG-CoA-reductase and who might thus be regulated by INSIG1 as well: •
Niemann-Pick disease type C1 protein, which participates in the intracellular movement of cholesterol •
Patched, the receptor for Hedgehog, a protein that contains covalently bound cholesterol
Oxysterols regulate cholesterol homeostasis through liver X receptor (
LXR) and sterol regulatory element-binding protein (
SREBP) mediated signaling pathway. This protein binds to the sterol-sensing domains of SREBP cleavage-activating protein (
SCAP) and
HMG CoA reductase, and is essential for the sterol-mediated trafficking of the two proteins. Alternatively spliced transcript variants encoding distinct isoforms have been observed. == Regulation ==