Inhibition of Apolipoprotein A-I Gene Expression by Obesity-Associated Endocannabinoids Article

International Collaboration

cited authors

  • Haas, Michael J., Mazza, Angela D., Wong, Norman C. W., Mooradian, Arshag D.

funding text

  • This work was supported by Dean's Fund Research Grant from the University of Florida-Jacksonville, FL. We thank Dr Ligaray and Elysia Heilig for their expertise in carrying out several of the experiments described in the manuscript.

abstract

  • Obesity is associated with increased serum endocannabinoid (EC) levels and decreased high-density lipoprotein cholesterol (HDLc). Apolipoprotein A-I (apo A-I), the primary protein component of HDL is expressed primarily in the liver and small intestine. To determine whether ECs regulate apo A-I gene expression directly, the effect of the obesity-associated ECs anandamide and 2-arachidonylglycerol on apo A-I gene expression was examined in the hepatocyte cell line HepG2 and the intestinal cell line Caco-2. Apo A-I protein secretion was suppressed nearly 50% by anandamide and 2-arachidonoylglycerol in a dose-dependent manner in both cell lines. Anandamide treatment suppressed both apo A-I mRNA and apo A-I gene promoter activity in both cell lines. Studies using apo A-I promoter deletion constructs indicated that repression of apo A-I promoter activity by anandamide requires a previously identified nuclear receptor binding site designated as site A. Furthermore, anandamide-treatment inhibited proteinDNA complex formation with the site A probe. Exogenous over expression of cannabinoid receptor 1 (CBR1) in HepG2 cells suppressed apo A-I promoter activity, while in Caco-2 cells, exogenous expression of both CBR1 and CBR2 could repress apo A-I promoter activity. The suppressive effect of anandamide on apo A-I promoter activity in Hep G2 cells could be inhibited by CBR1 antagonist AM251 but not by AM630, a selective and potent CBR2 inhibitor. These results indicate that ECs directly suppress apo A-I gene expression in both hepatocytes and intestinal cells, contributing to the decrease in serum HDLc in obese individuals.

Publication Date

  • April 1, 2012

webpage

published in

category

start page

  • 721

end page

  • 729

volume

  • 20

issue

  • 4

WoS Citations

  • 5

WoS References

  • 41