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

    Authors

    M. J. Haas; A. D. Mazza; N. C. W. Wong;A. D. Mooradian

    Comments

    Authors: contact us about adding a copy of your work at [email protected]

    Abbreviated Journal Title

    Obesity

    Keywords

    CARDIOMETABOLIC RISK-FACTORS; ACTIVATED RECEPTOR-ALPHA; HIGH-DENSITY-LIPOPROTEIN; CANNABINOID RECEPTOR; CB1 RECEPTORS; LIVER-CELLS; TNF-ALPHA; ANANDAMIDE; CHOLESTEROL; RIMONABANT; Endocrinology & Metabolism; Nutrition & Dietetics

    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.

    Journal Title

    Obesity

    Volume

    20

    Issue/Number

    4

    Publication Date

    1-1-2012

    Document Type

    Article

    Language

    English

    First Page

    721

    Last Page

    729

    WOS Identifier

    WOS:000302143300004

    ISSN

    1930-7381

    Share

    COinS
     

    Accessibility Statement

    This item was created or digitized prior to April 24, 2027, or is a reproduction of legacy media created before that date. It is preserved in its original, unmodified state specifically for research, reference, or historical recordkeeping. In accordance with the ADA Title II Final Rule, the University Libraries provides accessible versions of archival materials upon request. To request an accommodation for this item, please submit an accessibility request form.