Additive action of 11β-HSD1 inhibition and PPAR-γ agonism on hepatic steatosis and triglyceridemia in diet-induced obese rats

Berthiaume, Magalie; Laplante, Mathieu; Festuccia, William T.; Berger, Joel P.; Thieringer, Rolf; Deshaies, Yves

doi:10.1038/ijo.2009.33

Cited by 15 publications

(11 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The Merck Compound A decreased hepatic steatosis (with an additive effect when combined with rosiglitazone) (307,308). In addition, mice treated with antisense oligonucleotide knockdown of 11␤-HSD1 were protected from Western type diet-induced hepatic steatosis and dyslipidemia, with reduced synthesis and secretion of triglyceride and increased fatty acid oxidation.…”

Section: Animal Studiesmentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenase 1: Translational and Therapeutic Aspects

et al. 2013

View full text Add to dashboard Cite

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts the inactive glucocorticoid cortisone and its active form cortisol. It is widely expressed and, although bidirectional, in vivo it functions predominantly as an oxoreductase, generating active glucocorticoid. This allows glucocorticoid receptor activation to be regulated at a prereceptor level in a tissue-specific manner. In this review, we will discuss the enzymology and molecular biology of 11β-HSD1 and the molecular basis of cortisone reductase deficiencies. We will also address how altered 11β-HSD1 activity has been implicated in a number of disease states, and we will explore its role in the physiology and pathologies of different tissues. Finally, we will address the current status of selective 11β-HSD1 inhibitors that are in development and being tested in phase II trials for patients with the metabolic syndrome. Although the data are preliminary, therapeutic inhibition of 11β-HSD1 is also an exciting prospect for the treatment of a variety of other disorders such as osteoporosis, glaucoma, intracranial hypertension, and cognitive decline.

show abstract

Section: Animal Studiesmentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenase 1: Translational and Therapeutic Aspects

et al. 2013

View full text Add to dashboard Cite

show abstract

“…The majority of compounds used are still in early development with rodent models predominantly being used to assess safety and efficacy. There appears to be broad agreement that this approach is associated with decreased lipid accumulation and may have additive effects when combined with a Peroxisome Proliferative-Activated Receptor gamma agonist (117)(118)(119)(120). A novel study utilised a mouse model with an anti-sense oligonucleotide to knock down 11β-HSD1 with resulted in significant reduction in hepatic TAG synthesis and deposition and protection from a western style obesity diet (108).…”

Section: β-Hydroxysteroid-dehydrogenase Type 1 (11β-hsd1) Inhibitionmentioning

confidence: 99%

Glucocorticoids and non-alcoholic fatty liver disease

Woods

Hazlehurst

Tomlinson

2015

The Journal of Steroid Biochemistry and Molecular Biology

146

View full text Add to dashboard Cite

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the global obesity and metabolic disease epidemic and is rapidly becoming the leading cause of liver cirrhosis and indication for liver transplantation worldwide. The hallmark pathological finding in NAFLD is excess lipid accumulation within hepatocytes, but it is a spectrum of disease ranging from benign hepatic steatosis to steatohepatitis through to fibrosis, cirrhosis and risk of hepatocellular carcinoma. The exact pathophysiology remains unclear with a multi-hit hypothesis generally accepted as being required for inflammation and fibrosis to develop after initial steatosis. Glucocorticoids have been implicated in the pathogenesis of NAFLD across all stages. They have a diverse array of metabolic functions that have the potential to drive NAFLD acting on both liver and adipose tissue. In the fasting state, they are able to mobilize lipid, increasing fatty acid delivery and in the fed state can promote lipid accumulation. Their action is controlled at multiple levels and in this review will outline the evidence base for the role of GCs in the pathogenesis of NAFLD from cell systems, rodent models and clinical studies and describe interventional strategies that have been employed to modulate glucocorticoid action as a potential therapeutic strategy.

show abstract

“…However, there was no change in size of the more metabolically favorable epididymal fat pad where, in sharp contrast to the mesenteric depot, expression of genes involved in lipogenesis were increased [88,89]. Compound A has also been used in combination with TZD where it further decreased liver lipid levels compared to TZD alone, and tended towards a further decrease in serum lipid levels [90].…”

Section: Rodent Studiesmentioning

confidence: 99%