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[Disorder of cholesterol metabolism: regulation of intracellular cholesterol and membrane trafficking].

Abstract
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.
AuthorsNaoki Tamasawa
JournalRinsho byori. The Japanese journal of clinical pathology (Rinsho Byori) Vol. 58 Issue 12 Pg. 1203-10 (Dec 2010) ISSN: 0047-1860 [Print] Japan
PMID21348240 (Publication Type: English Abstract, Journal Article, Review)
Chemical References
  • Basic Helix-Loop-Helix Transcription Factors
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Multiprotein Complexes
  • SREBP cleavage-activating protein
  • Sterol Regulatory Element Binding Proteins
  • Cholesterol
  • Acetyl-CoA C-Acyltransferase
Topics
  • Acetyl-CoA C-Acyltransferase (physiology)
  • Basic Helix-Loop-Helix Transcription Factors
  • Biological Transport
  • Cell Membrane (metabolism)
  • Cholesterol (metabolism)
  • Endoplasmic Reticulum (metabolism)
  • Golgi Apparatus (metabolism)
  • Humans
  • Intracellular Signaling Peptides and Proteins (physiology)
  • Lipid Metabolism Disorders (etiology, metabolism)
  • Membrane Proteins (physiology)
  • Multiprotein Complexes
  • Niemann-Pick Diseases (etiology, metabolism)
  • Sterol Regulatory Element Binding Proteins (physiology)
  • Tangier Disease (etiology, metabolism)

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