Event:54

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Event Title

CD36, Up Regulation
Short name: CD36, Up Regulation

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
LXR activation leading to hepatic steatosis KE
NR1I3 (CAR) suppression leading to hepatic steatosis KE Strong
AhR activation leading to hepatic steatosis KE Strong
NR1I2 (Pregnane X Receptor, PXR) activation leading to hepatic steatosis KE Strong

Taxonomic Applicability

Name Scientific Name Evidence Links

Level of Biological Organization

Biological Organization

How this Key Event works

Fatty acid translocase CD36 (FAT/CD36) is a scavenger protein mediating uptake and intracellular transport of long-chain fatty acids (FA) in diverse cell types [1], [2]. In addition, CD36 can bind a variety of molecules including acetylated low density lipoproteins (LDL), collagen and phospholipids [3]. CD36 has been shown to be expressed in liver tissue [4], [5]. It is located in lipid rafts and non-raft domains of the cellular plasma membrane and most likely facilitates LCFA transport by accumulating LCFA on the outer surface [6], [7], [8].

FAT/CD36 gene is a liver specific target of LXR activation [9]. Studies have confirmed that the lipogenic effect of LXR and activation of FAT/CD36 was not a simple association, since the effect of LXR agonists on increasing hepatic and circulating levels of triglycerides and free fatty acids (FFAs) was largely abolished in FAT/CD36 knockout mice suggesting that intact expression and/or activation of FAT/CD36 is required for the steatotic effect of LXR agonists [10], [11]. In addition to the well-defined pathogenic role of FAT/CD36 in hepatic steatosis in rodents the human up-regulation of the FAT/CD36 in NASH patients is confirmed [12]. There are now findings that can accelerate the translation of FAT/CD36 metabolic functions determined in rodents to humans [13] and suggest that the translocation of this fatty acid transporter to the plasma membrane of hepatocytes may contribute to liver fat accumulation in patients with NAFLD and HCV [14]. In addition, hepatic FAT/CD36 up-regulation is significantly associated with insulin resistance, hyperinsulinaemia and increased steatosis in patients with NASH and HCV G1 (Hepatitis C Virus Genotype1) with fatty liver. Recent data show that CD36 is also increased in the liver of morbidly obese patients and correlated to free FA levels [15].

How it is Measured or Detected

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

Evidence Supporting Taxonomic Applicability

References

  1. Su & Abumrad 2009
  2. He et al. 2011
  3. Krammer 2011
  4. Pohl et al. 2005
  5. Cheung et al. 2007
  6. Ehehalt et al. 2008
  7. Pohl et al. 2005
  8. Krammer 2011
  9. Zhou 2008
  10. Febbraio et al. 1999
  11. Lee et al. 2008
  12. Zhu et al. 2011
  13. Love-Gregory et al. 2011
  14. Miquilena-Colina et al. 2011
  15. Bechmann et al. 2010