Inhibition of apolipoprotein A-I gene expression by obesity-associated endocannabinoids

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 protein-DNA 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.     

Age-related changes in the thyroid hormone effects on malondialdehyde-modified proteins in the rat heart.

To determine the age-related changes in thyroid hormone (TH) effects on malondialdehyde (MDA)-modified proteins in cardiac tissue, rats at 4, 12, and 25 months of age were studied. Hyperthyroidism was induced with daily injection of L-triiodothyronine (15 microg/100 g) intraperitoneally for 10 days. Hypothyroidism was induced with 0. 025% methimazole in the drinking water for 4 weeks. MDA proteins were measured with immunoblots using a specific anti-MDA antiserum. MDA was measured as thiobarbituric acid reactive substance. Hypothyroidism in 4-month-old rats was associated with significant reduction in MDA proteins compared to euthyroid rats (13.4 +/- 5.9% vs. 99.8 +/- 10.4% of controls P < 0.001). Hyperthyroidism did not result in a significant change of MDA proteins. In aged rats, neither hypothyroidism nor hyperthyroidism was associated with significant changes in cardiac MDA proteins. The changes in MDA proteins did not correlate with cardiac MDA concentrations. In young rats, the MDA concentrations (nmol/mg) were significantly reduced in hypothyroidism (2.71 +/- 0.21) and were increased in hyperthyroidism (8.19 +/- 0.78) compared to euthyroid values (5.06 +/- 0.71) P < 0. 01. In aged rats, cardiac MDA content was significantly increased during both hyperthyroidism and hypothyroidism. We conclude that alterations in MDA protein content is yet another potential biochemical effect of TH in cardiac tissue. This particular effect is significantly blunted with age.     

Ethane production rate in vivo is reduced with dietary restriction

Dietary restriction without malnutrition prolongs life and has a beneficial effect on age-related diseases and metabolic derangements. To test the effect of food restriction on ethane production rate, ethane exhalation was measured in rats with partial food restriction. Ethane production rate in room air in rats fed 60% of food consumed by ad libitum-fed animals for 2 wk was significantly reduced (3.50 +/- 0.25 vs. 5.21 +/- 0.34 pmol.min-1.100 g body wt-1, P less than 0.01). In 100% oxygen, ethane production in food-restricted rats was not different from that of ad libitum-fed rats (21.81 +/- 1.25 vs. 19.57 +/- 1.89 pmol.min-1.100 g-1). Fifteen hours of fasting compared with ad libitum feeding reduced ethane production modestly in room air (4.37 +/- 0.45 vs. 5.21 +/- 0.34 pmol.min-1.100 g-1) and more significantly in 100% oxygen (12.37 +/- 0.78 vs. 19.57 +/- 1.89 pmol.min-1.100 g-1). Thus, in 100% oxygen, 15 h of fasting, compared with ad libitum feeding, resulted in an approximately 40% decrease in ethane production rate. It is concluded that short-term food restriction significantly reduces ethane exhalation rate in rats when measured in room air.     

Cancer-associated exportin-6 upregulation inhibits the transcriptionally repressive and anticancer effects of nuclear profilin-1

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