Bezafibrate regulates the expression and enzyme activity of 11β-hydroxysteroid dehydrogenase type 1 in murine adipose tissue and 3T3-L1 adipocytes

Abstract

regulates the expression and enzyme activity of 11␤-hydroxysteroid dehydrogenase type 1 in murine adipose tissue and 3T3-L1 adipocytes. Am J Physiol Endocrinol Metab 292: E1213-E1222, 2007. First published December 26, 2006; doi:10.1152/ajpendo.00340.2006.-A clinically employed antihyperlipidemic drug, bezafibrate, has been characterized as a PPAR(␣, -␥, and -␦) pan-agonist in vitro. Recent extended trials have highlighted its antidiabetic properties in humans. However, the underlying molecular mechanism is not fully elucidated. The present study was designed to explore potential regulatory mechanisms of intracellular glucocorticoid reactivating enzyme, 11␤-HSD1 and anti-diabetic hormone, adiponectin by bezafibrate in murine adipose tissue, and cultured adipocytes. Treatment of db/db mice with bezafibrate significantly ameliorated hyperglycemia and insulin resistance, accompanied by a marked reduction of triglyceride and nonesterified fatty acids. Despite equipotent in lipid-lowering effects, another fibrate, fenofibrate, did not show such beneficial effects on glycemic control. Treatment of bezafibrate caused a marked decrease in the mRNA level of 11␤-HSD1 preferentially in adipose tissue of db/db mice (Ϫ47%, P Ͻ 0.05), concomitant with a significant increase in plasma adiponectin level (ϩ37%, P Ͻ 0.01). Notably, treatment of bezafibrate caused a marked decrease in the mRNA level (Ϫ34%, P Ͻ 0.01) and enzyme activity (Ϫ32%, P Ͻ 0.01) of 11␤-HSD1, whereas the treatment substantially augmented the expression (ϩ71%, P Ͻ 0.01) and secretion (ϩ27%, P Ͻ 0.01) of adiponectin in 3T3-L1 adipocytes. Knockdown of 11␤-HSD1 by siRNA confirmed that 11␤-HSD1 acts as a distinct oxoreductase in adipocytes and validated the enzyme activity assays in the present study. Effects of bezafibrate on regulation of 11␤-HSD1 and adiponectin in murine adipocytes were comparable with those in thiazolidinediones. This is the first demonstration that bezafibrate directly regulates 11␤-HSD1 and adiponectin in murine adipocytes, both of which may contribute to metabolicallybeneficial effects by bezafibrate. metabolic syndrome; adiponectin FAMILY GENES of peroxisome proliferator-activated receptors (PPARs) are profoundly relevant to fuel homeostasis (14, 41). Agonists for PPAR␣ and PPAR␥ have been widely used for the treatment of dyslipidemia and type 2 diabetes (46). Recent research progress (3) has highlighted the potential usefulness of PPAR␣/␥ dual agonists or PPAR(␣, -␥, and -␦) pan-agonists for metabolic diseases. However, some of these compounds are reported to cause adverse effects, including carcinogenesis, edema, hepatotoxicity, and increase in body weight in rodent experiments (45). Bezafibrate has been widely used for the treatment of dyslipidemia in human clinics (11). Recent in vitro experiments have shown that bezafibrate serves as a pan-agonist for PPAR␣, -␥, and -␦ (9, 48). Furthermore, recent extended clinical trials (15, 43) have highlighted its antidiabetic properties. However, the underlying mechanism is not fully clarified...

The effects of branched-chain amino acid granules on the accumulation of tissue triglycerides and uncoupling proteins in diet-induced obese mice

“…The exact function of PPARalpha in WAT has not received much attention because its expression level is lower compared with liver and muscle tissues. Nevertheless, our current data and the results of previous studies have identified the expression of PPAR-alpha in WAT and 3T3-L1 adipocytes [27]. The role of WAT PPAR-alpha in fatty acid oxi-mice by the changes of UCP2 and UCP3.…”

Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease

“…However, it was not clear whether the therapeutic benefit was related to benzafibrate or to a 1000 kilocalorie/day diet and a 600 kilocalorie/day exercise regimen. In addition to being a PPARα ligand, benzofibrate activates PPARγ and improves insulin sensitivity in animal models [46,47] , an effect not seen with fenofibrate [50] . Another study demonstrated that 42% of 62 patients with NAFLD had biochemical and ultrasound improvement on fenofibrate, but histologic data were not collected [51] .…”

11β-hydroxysteroid dehydrogenase type 1 gene expression is increased in ascending aorta tissue of metabolic syndrome patients with coronary artery disease

“…Factors influencing 11β-HSD-1 expression include GCs, insulin, thyroid hormones, sex steroids, GH, IGF-1, cytokines and differentiation, determination and transcription factors such as PPARg2, C/EBPα, SREBP1c/ADD1, SPARC, NFkappaB, Stat5, or FOXO binding sites. PPARg agonists have indeed been found to modify the expression and the activity of 11β-HSD-1 in adipose tissue (Nakano et al, 2007;Kolak et al, 2007).…”