Abstract | BACKGROUND & AIMS: METHODS: RESULTS: The CDAA diet induced NASH in WT mice, characterized by steatosis, inflammation, fibrosis, and insulin resistance. TLR9(-/-) mice showed less steatohepatitis and liver fibrosis than WT mice. Among inflammatory cytokines, IL-1beta production was suppressed in TLR9(-/-) mice. Kupffer cells produced IL-1beta in response to CpG oligodeoxynucleotide. IL-1beta but not CpG- oligodeoxynucleotides, increased lipid accumulation in hepatocytes. Lipid accumulation in hepatocytes led to nuclear factor-kappaB inactivation, resulting in cell death in response to IL-1beta. IL-1beta induced fibrogenic responses in HSCs, including secretion of tissue inhibitor of metalloproteinase-1. IL-1R(-/-) mice had reduced steatohepatitis and fibrosis, compared with WT mice. Mice deficient in MyD88, an adaptor molecule for TLR9 and IL-1R signaling, also had reduced steatohepatitis and fibrosis. TLR9(-/-), IL-1R(-/-), and MyD88(-/-) mice had less insulin resistance than WT mice on the CDAA diet. CONCLUSIONS: In a mouse model of NASH, TLR9 signaling induces production of IL-1beta by Kupffer cells, leading to steatosis, inflammation, and fibrosis.
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Authors | Kouichi Miura, Yuzo Kodama, Sayaka Inokuchi, Bernd Schnabl, Tomonori Aoyama, Hirohide Ohnishi, Jerrold M Olefsky, David A Brenner, Ekihiro Seki |
Journal | Gastroenterology
(Gastroenterology)
Vol. 139
Issue 1
Pg. 323-34.e7
(Jul 2010)
ISSN: 1528-0012 [Electronic] United States |
PMID | 20347818
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Interleukin-1beta
- Myd88 protein, mouse
- Myeloid Differentiation Factor 88
- RNA, Messenger
- Tlr9 protein, mouse
- Toll-Like Receptor 9
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Topics |
- Animals
- Choline Deficiency
(complications)
- Fatty Liver
(etiology)
- Hepatic Stellate Cells
(physiology)
- Insulin Resistance
- Interleukin-1beta
(genetics, physiology)
- Kupffer Cells
(physiology)
- Lipid Metabolism
- Liver Cirrhosis, Experimental
(etiology)
- Male
- Mice
- Mice, Inbred C57BL
- Myeloid Differentiation Factor 88
(physiology)
- RNA, Messenger
(analysis)
- Signal Transduction
- Toll-Like Receptor 9
(physiology)
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