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c-Jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis to steatohepatitis and fibrosis in mice.
- Source :
-
Gastroenterology [Gastroenterology] 2009 Oct; Vol. 137 (4), pp. 1467-1477.e5. Date of Electronic Publication: 2009 Jun 21. - Publication Year :
- 2009
-
Abstract
- Background & Aims: c-Jun N-terminal kinase (JNK) plays a pivotal role in the development of the metabolic syndrome including nonalcoholic fatty liver disease. However, the mechanism underlying the contribution of JNK to the progression from simple steatosis to steatohepatitis and liver fibrosis is unresolved.<br />Methods: Hepatic steatosis, inflammation, and fibrosis were examined in wild-type, jnk1(-/-), or jnk2(-/-) mice fed a choline-deficient L-amino acid-defined (CDAA) diet for 20 weeks. The functional contribution of JNK isoforms in Kupffer cells was assessed in vitro and in vivo using chimeric mice in which the hematopoietic compartment including Kupffer cells was replaced by wild-type, jnk1(-/-), or jnk2(-/-) cells.<br />Results: CDAA diet induced significantly less hepatic inflammation and less liver fibrosis despite a similar level of hepatic steatosis in jnk1(-/-) mice as compared with wild-type or jnk2(-/-) mice. CDAA diet-induced hepatic inflammation was chronic and mediated by Kupffer cells. Pharmacologic inhibition of JNK or gene deletion of jnk1 but not jnk2 repressed the expression of inflammatory and fibrogenic mediators in primary Kupffer cells. In vivo, CDAA diet induced less hepatic inflammation and liver fibrosis despite an equivalent level of hepatic steatosis in chimeric mice with jnk1(-/-) hematopoietic cells as compared with chimeric mice with wild-type or jnk2(-/-) hematopoietic cells.<br />Conclusions: jnk1(-/-) mice are resistant to diet-induced steatohepatitis and liver fibrosis. JNK1 in hematopoietic cells, especially in Kupffer cells, contributes to the development of liver fibrosis by inducing chronic inflammation.
- Subjects :
- Animals
Bone Marrow Cells drug effects
Bone Marrow Cells immunology
Bone Marrow Cells pathology
Bone Marrow Transplantation
Cells, Cultured
Chimera
Choline Deficiency complications
Choline Deficiency enzymology
Disease Progression
Fatty Liver enzymology
Fatty Liver immunology
Fatty Liver prevention & control
Hepatitis, Chronic enzymology
Hepatitis, Chronic etiology
Inflammation Mediators metabolism
Kupffer Cells drug effects
Kupffer Cells immunology
Kupffer Cells pathology
Liver drug effects
Liver immunology
Liver pathology
Liver Cirrhosis, Experimental enzymology
Liver Cirrhosis, Experimental immunology
Liver Cirrhosis, Experimental prevention & control
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitogen-Activated Protein Kinase 8 antagonists & inhibitors
Mitogen-Activated Protein Kinase 8 deficiency
Mitogen-Activated Protein Kinase 8 genetics
Mitogen-Activated Protein Kinase 9 genetics
Mitogen-Activated Protein Kinase 9 metabolism
Protein Kinase Inhibitors pharmacology
RNA, Messenger metabolism
Signal Transduction
Time Factors
Bone Marrow Cells enzymology
Fatty Liver etiology
Kupffer Cells enzymology
Liver enzymology
Liver Cirrhosis, Experimental etiology
Mitogen-Activated Protein Kinase 8 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0012
- Volume :
- 137
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 19549522
- Full Text :
- https://doi.org/10.1053/j.gastro.2009.06.045