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Publication
Carbenoxolone treatment attenuates symptoms of metabolic syndrome and
atherogenesis in obese, hyperlipidemic mice.
Authors Nuotio-Antar AM, Hachey D, Hasty AH
Submitted By Alyssa Hasty on 11/12/2007
Status Published
Journal American journal of physiology. Endocrinology and metabolism
Year 2007
Date Published
Volume : Pages 293(6) : E1517 - E1528
PubMed Reference 17878220
Abstract Glucocorticoids, which are well established to regulate body fat mass
distribution, adipocyte lipolysis, hepatic gluconeogenesis, and hepatocyte VLDL
secretion, are speculated to play a role in the pathology of metabolic syndrome.
Recent focus has been on the activity of 11beta-hydroxysteroid dehydrogenase
type 1 (11beta-HSD1), which is capable of regenerating, and thus amplifying,
glucocorticoids in key metabolic tissues such as liver and adipose tissue. To
determine the effects of global 11beta-HSD1 inhibition on metabolic syndrome
risk factors, we subcutaneously injected Western-type diet-fed hyperlipidemic
mice displaying either moderate or severe obesity (LDLR-/- and Agouti;LDLR-/-,
respectively) with the nonselective 11beta-HSD inhibitor carbenoxolone for 4
weeks. Body composition throughout the study, end-point fasting plasma analyses,
and extent of hepatic steatosis and atherosclerosis were assessed. This route of
treatment led to high levels of carbenoxolone detected in liver and fat and
resulted in decreased weight gain due to reduced body fat mass in both mouse
models. However, only Agouti;LDLR-/- mice showed an effect of 11beta-HSD1
inhibition on fasting insulin and plasma lipids, coincident with a reduction in
VLDL due to mildly increased VLDL clearance and dramatically decreased hepatic
triglyceride production. Agouti;LDLR-/- mice also showed the greatest effect of
the drug on reducing atherosclerotic lesion formation. These findings indicate
that subcutaneous injection of an 11beta-HSD1 inhibitor allows for the targeting
of the enzyme in not only liver, but also adipose tissue and attenuates many
metabolic syndrome risk factors, with more pronounced effects in cases of severe
obesity and hyperlipidemia. Key words: 11 beta hydroxysteroid dehydrogenase,
agouti, obese, low density lipoprotein receptor deficient.




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