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Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptin-mediated signaling.
- Source :
-
Cell metabolism [Cell Metab] 2012 Jul 03; Vol. 16 (1), pp. 44-54. - Publication Year :
- 2012
-
Abstract
- Although bacterial endotoxin, such as lipopolysaccharide (LPS), plays a key role in the pathogenesis of nonalcoholic steatohepatitis (NASH), detailed mechanisms of this pathogenesis remain unclear. Here, we demonstrate that upregulation of CD14 by leptin-mediated signaling is critical to hyperreactivity against endotoxin during NASH progression. Upregulation of CD14 in Kupffer cells and hyperreactivity against low-dose LPS were observed in high-fat diet (HFD)-induced steatosis mice, but not chow-fed-control mice. Hyperresponsivity against low-dose LPS led to accelerated NASH progression, including liver inflammation and fibrosis. Administering leptin in chow-fed mice caused increased hepatic expression of CD14 via STAT3 signaling, resulting in hyperreactivity against low-dose LPS without steatosis. In contrast, a marked decrease in hepatic CD14 expression was observed in leptin-deficient ob/ob mice, despite severe steatosis. Our results indicate that obesity-induced leptin plays a crucial role in NASH progression via enhanced responsivity to endotoxin, and we propose a mechanism of bacteria-mediated progression of NASH.<br /> (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Subjects :
- Alanine Transaminase blood
Animals
Cell Line
Cytokines blood
Cytokines genetics
Cytokines metabolism
Diet, High-Fat adverse effects
Fatty Liver etiology
Fatty Liver immunology
Gene Expression
Hepatitis, Animal etiology
Hepatitis, Animal immunology
Hepatitis, Animal metabolism
Hepatitis, Animal pathology
Humans
Leptin physiology
Lipopolysaccharide Receptors genetics
Lipopolysaccharide Receptors metabolism
Liver Cirrhosis
Liver Cirrhosis, Experimental etiology
Liver Cirrhosis, Experimental immunology
Liver Cirrhosis, Experimental metabolism
Liver Cirrhosis, Experimental pathology
Male
Mice
Mice, Inbred C57BL
Mice, Obese
Non-alcoholic Fatty Liver Disease
STAT3 Transcription Factor metabolism
Toll-Like Receptor 4 genetics
Toll-Like Receptor 4 metabolism
Tumor Necrosis Factor-alpha metabolism
Fatty Liver metabolism
Fatty Liver pathology
Leptin metabolism
Lipopolysaccharides pharmacology
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1932-7420
- Volume :
- 16
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cell metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 22768838
- Full Text :
- https://doi.org/10.1016/j.cmet.2012.05.012