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

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    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

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