PPARα Agonists Reduce 11β-Hydroxysteroid Dehydrogenase Type 1 in the Liver

Hermanowski‐Vosatka, Anne; Gerhold, David; Mundt, Steven S.; Loving, Vilert A.; Lu, Meiqing; Chen, Yuli; Elbrecht, Alex; Wu, Margaret; Doebber, Thomas W.; Kelly, Linda; Milot, Denise P.; Guo, Qiu; Wang, Pei-Ran; Ippolito, Marc C.; Chao, Yu‐Sheng; Wright, Samuel D.; Thieringer, Rolf

doi:10.1006/bbrc.2000.3966

Cited by 92 publications

(54 citation statements)

References 23 publications

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“…3A). These effects may also explain unidentified, metabolically beneficial properties of fibrates (13,25), because transgenic mice overexpressing 11␤-HSD1 exclusively in liver exemplify fatty liver, glucose intolerance, dyslipidemia, and severe hypertension (36). In this context, the potential pathophysiological role of 11␤-HSD1 in liver must await further investigation.…”

Section: Discussionmentioning

confidence: 99%

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

Nakano¹,

Inada²,

Masuzaki³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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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...

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Section: Discussionmentioning

confidence: 99%

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

Nakano¹,

Inada²,

Masuzaki³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

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“…In rodents PPARα agonists decrease hepatic 11βHSD1 expression, while PPARγ agonists reduce 11βHSD1 expression and activity in adipose tissue [66,67]. In humans, although treatment for 1 week with fenofibrate or rosiglitazone had no effect on liver or adipose 11βHSD1 activity [68], treatment with thiazolidinedione for 8-12 weeks has been associated with reduced adipose tissue 11βHSD1 in some [66,68], but not all [69], studies.…”

Section: Physiological and Pharmacological Regulation Of 11βhsd1mentioning

confidence: 99%

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

et al. 2014

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Cushing's syndrome, caused by increased production of cortisol, leads to metabolic dysfunction including visceral adiposity, hypertension, hyperlipidaemia and type 2 diabetes. The similarities with the metabolic syndrome are striking and major efforts have been made to find obesityassociated changes in the regulation of glucocorticoid action and synthesis, both at a systemic level and tissue level. Obesity is associated with tissue-specific alterations in glucocorticoid metabolism, with increased activity of the glucocorticoidregenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in subcutaneous adipose tissue and decreased conversion of cortisone to cortisol, interpreted as decreased 11βHSD1 activity, in the liver. In addition, genetic manipulation of 11βHSD1 activity in rodents can either induce (by overexpression of Hsd11b1, the gene encoding 11βHSD1) or prevent (by knocking out Hsd11b1) obesity and metabolic dysfunction. Taken together with earlier evidence that non-selective inhibitors of 11βHSD1 enhance insulin sensitivity, these results led to the hypothesis that inhibition of 11βHSD1 might be a promising target for treatment of the metabolic syndrome. Several selective 11βHSD1 inhibitors have now been developed and shown to improve metabolic dysfunction in patients with type 2 diabetes, but the small magnitude of the glucose-lowering effect has precluded their further commercial development.This review focuses on the role of 11βHSD1 as a tissuespecific regulator of cortisol exposure in obesity and type 2 diabetes in humans. We consider the potential of inhibition of 11βHSD1 as a therapeutic strategy that might address multiple complications in patients with type 2 diabetes, and provide our thoughts on future directions in this field.

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“…Thus, PPARγ agonists could mediate at least part of their beneficial effect on insulin sensitivity by downregulation of 11β-HSD1. Also agonists of PPARα mainly expressed in liver, down-regulate 11β-HSD1 expression and activity in livers of wild-type but not of PPARα −/− mice [84]. However, PPARα agonists do not have a relevant effect on insulin sensitivity in diabetic patients perhaps because hepatic 11β-HSD1 expression appears already down-regulated in visceral obesity [23].…”

Section: Down-regulation Of 11β-hsd1 Expressionmentioning

confidence: 99%

11?-Hydroxysteroid dehydrogenase Type 1 in obesity and Type 2 diabetes

2004

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Obesity and Type 2 diabetes mellitus are associated with abnormal regulation of glucocorticoid metabolism that are highlighted by clinical similarities between the sequelae of insulin resistance and Cushing's syndrome, as well as glucocorticoids' functional antagonism to insulin. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates functionally inert glucocorticoid precursors (cortisone) to active glucocorticoids (cortisol) within insulin target tissues, such as adipose tissue, thereby regulating local glucocorticoid action. Recent data, mainly from rodents, provide considerable evidence for a causal role of 11β-HSD1 for the development of visceral obesity and Type 2 diabetes though data in humans are not unequivocal. This review summarizes current evidence on a possible role of 11β-HSD1 for development of the metabolic syndrome, raising the possibility of novel therapeutic options for the treatment of Type 2 diabetes by inhibition or down-regulation of 11β-HSD1 activity.[Diabetologia (2004) by increased waist-to-hip ratio-rather than lowerbody (gynoid) obesity is associated with glucose intolerance and other features of the metabolic syndrome, and represents an important predictor for increased morbidity and mortality, not only from diabetes but also from coronary heart disease and certain cancers [4]. Although the WHR encompasses both intra-abdominal (visceral) and abdominal subcutaneous adipose depots, more detailed studies emphasize the importance of the visceral component for the development of metabolic disorders [4]. A causal relationship of visceral obesity for insulin resistance was recently demonstrated by surgical removal of visceral (epididymal and perinephric) fat pads of obese Sprague-Dawley rats that markedly improved hepatic insulin sensitivity and reduced hepatic glucose production [5].

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PPARα Agonists Reduce 11β-Hydroxysteroid Dehydrogenase Type 1 in the Liver

Cited by 92 publications

References 23 publications

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

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

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

11?-Hydroxysteroid dehydrogenase Type 1 in obesity and Type 2 diabetes

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