Antagonism of central melanin-concentrating hormone 1 receptor alleviates steatohepatitis in mice
| Autor: | Akane Ishihara, Akira Gomori, Masao Matsuda, Minoru Sasaki, Maria A. Bednarek, Douglas J. MacNeil, Masahiko Ito, Shigeharu Tsujioka, Hisashi Iwaasa, Akio Kanatani, Jun Suzuki, Makoto Ito |
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| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty Endocrinology Diabetes and Metabolism Interleukin-1beta Biology Polymerase Chain Reaction Collagen Type I Mice chemistry.chemical_compound Endocrinology Internal medicine medicine Hyperinsulinemia Animals Obesity Receptors Pituitary Hormone Receptor Chemokine CCL2 Triglycerides Hepatitis Methionine Tumor Necrosis Factor-alpha Body Weight Fatty liver Antagonist medicine.disease Dietary Fats Collagen Type I alpha 1 Chain Fatty Liver Mice Inbred C57BL Disease Models Animal Gene Expression Regulation Liver chemistry Steatohepatitis Hormone |
| Zdroj: | Journal of Endocrinology. 198:309-315 |
| ISSN: | 1479-6805 0022-0795 |
| DOI: | 10.1677/joe-08-0087 |
| Popis: | Blockade of brain melanin-concentrating hormone 1 receptor (MCH1R) significantly ameliorates fatty liver as well as obesity. However, the mode of action of this effect is unknown. This study examined the effect of a MCH1R antagonist in murine steatohepatitis models with and without obesity and clarified whether these pharmacological effects were attributed to anti-obesity effects. Steatohepatitis with concomitant obese phenotypes was developed after 52-week exposure to a high-fat diet, and steatohepatitis with reduced body weight was developed by exposure to a methionine- and choline-deficient diet for 10 days. Chronic intracerebroventricular infusion of a peptidic MCH1R antagonist reduced hepatic triglyceride contents and ameliorated steatohepatitis on histological observations in both mice models. Improvement of steatohepatitis was concomitant with amelioration of obese phenotypes such as hyperinsulinemia and hyperleptinemia in the case of the obese model, whereas body weight reduction was not associated with amelioration of steatohepatitis by the antagonist in the lean model. Reduction of hepatic gene expressions encoding cytochromes P450 4A was identified by treatment with the antagonist in both the obese and lean models. These results suggest that brain blockade of MCH1R could alleviate steatohepatitis independently from anti-obesity effects. In conclusion, MCH1R antagonist could have a new therapeutic potential for the treatment of human nonalcoholic steatohepatitis. |
| Databáze: | OpenAIRE |
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