c-Jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis to steatohepatitis and fibrosis in mice.

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.

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.

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.

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.

• Authors: Yuzo Kodama, Tatiana Kisseleva, Keiko Iwaisako, Kouichi Miura, Kojiro Taura, Samuele De Minicis, Christoph H Osterreicher, Bernd Schnabl, Ekihiro Seki, David A Brenner
• Journal: Gastroenterology (Gastroenterology) Vol. 137 Issue 4 Pg. 1467-1477.e5 (Oct 2009) ISSN: 1528-0012 [Electronic] United States
• PMID: 19549522 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Inflammation Mediators
• Protein Kinase Inhibitors
• RNA, Messenger
• Mitogen-Activated Protein Kinase 9
• Mitogen-Activated Protein Kinase 8

Topics

• Animals
• Bone Marrow Cells (drug effects, enzymology, immunology, pathology)
• Bone Marrow Transplantation
• Cells, Cultured
• Chimera
• Choline Deficiency (complications, enzymology)
• Disease Progression
• Fatty Liver (enzymology, etiology, immunology, prevention & control)
• Hepatitis, Chronic (enzymology, etiology)
• Inflammation Mediators (metabolism)
• Kupffer Cells (drug effects, enzymology, immunology, pathology)
• Liver (drug effects, enzymology, immunology, pathology)
• Liver Cirrhosis, Experimental (enzymology, etiology, immunology, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitogen-Activated Protein Kinase 8 (antagonists & inhibitors, deficiency, genetics, metabolism)
• Mitogen-Activated Protein Kinase 9 (genetics, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• RNA, Messenger (metabolism)
• Signal Transduction
• Time Factors