It has been clarified that several
transcription factors and functioning
proteins play important roles regulating intracellular
cholesterol levels. They bind to the ER membrane and sense changes in
cholesterol levels in the membrane through
SSD. An important membrane-binding
transcription factor, SREBP, is retained in the ER membrane, forming an SREBP/SCAP/INSIG trimer when cellular
cholesterol levels are abundant. This complex blocks the transport of SREBPs to the Golgi apparatus, thus preventing subsequent transcriptional activation. When cellular
cholesterol levels are low, the ER
cholesterol concentration is below a threshold value ( <5 mol %). Under these conditions, SCAP escorts SREBPs from the ER to Golgi apparatus by binding to a component of the CopII
protein coat. Once in the Golgi apparatus, the SREBPs are proteolytically processed to generate their nuclear form, the bHLH leucine zipper, that activates genes for
cholesterol synthesis and uptake.
HMG-CoA reductase is also post-transcriptionally regulated by
sterol, with INSIG binding of the
protein leading to its proteosomal degradation. We demonstrated that
Tangier disease and
Niemann-Pick disease type B and type C are metabolic disorders of membrane
cholesterol. These diseases are not so common in clinical medicine; however, it is very important to understand
membrane lipid metabolism, especially in the ER. It will be clarified in the near future disorders of membrane
cholesterol trafficking contribute to the pathogeneses of many kinds of disease affecting through ER functioning.