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- Title
Mixed lineage kinase 3 deficient mice are protected against the high fat high carbohydrate diet-induced steatohepatitis.
- Authors
Ibrahim, Samar H.; Gores, Gregory J.; Hirsova, Petra; Kirby, Michelle; Miles, Lili; Jaeschke, Anja; Kohli, Rohit
- Abstract
Background & Aims C-Jun N-terminal kinase ( JNK) activation is pivotal in the development of nonalcoholic steatohepatitis ( NASH). Mixed lineage kinase 3 ( MLK) 3 is one of the mitogen activated protein kinase kinase kinase ( MAP3K) that mediates JNK activation in the liver. Despite this concept, the role of MLK3 in modulating liver injury during nutrient excess has not been explored. Our aim was to determine if MLK3 deficient mice were protected against high fat high carbohydrate ( HFHC) diet-induced NASH. Methods We employed eight-week-old Mlk3−/− male C57 BL/6J mice, and wild type ( WT) mice C57 BL/6J as controls. Mice were fed a HFHC or a chow diet adlib for 16 weeks. Results Hepatic JNK activating phosphorylation was readily absent in the Mlk3 −/− mice fed the HFHC diet, but not in WT mice. This inhibition of JNK activation was hepatoprotective. Despite a comparable increase in weight gain, hepatic steatosis by histological examination and hepatic triglyceride quantification was reduced in HFHC diet-fed Mlk3 −/− mice compared with WT mice. In addition, compared with the WT mice, HFHC diet-fed Mlk3 −/− mice had significantly attenuated liver injury as manifested by reduced ALT levels, hepatocyte apoptosis, markers of hepatic inflammation and indices of hepatic fibrogenesis. Conclusion Our results suggest that loss of MLK3 in mice is protective against HFHC diet-induced NASH, in a weight-independent fashion, through attenuation of JNK activation. MLK3 is a potential therapeutic target for the treatment of human NASH.
- Subjects
PROTEIN kinase regulation; FATTY liver; TRIGLYCERIDES; APOPTOSIS; INFLAMMATION
- Publication
Liver International, 2014, Vol 34, Issue 3, p427
- ISSN
1478-3223
- Publication type
Article
- DOI
10.1111/liv.12353