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Mixed lineage kinase 3 deficient mice are protected against the high fat high carbohydrate diet‐induced steatohepatitis
Author(s) -
Ibrahim Samar H.,
Gores Gregory J.,
Hirsova Petra,
Kirby Michelle,
Miles Lili,
Jaeschke Anja,
Kohli Rohit
Publication year - 2014
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12353
Subject(s) - endocrinology , medicine , steatohepatitis , steatosis , kinase , fatty liver , protein kinase a , biology , chemistry , biochemistry , disease
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 ( MAP 3K) that mediates JNK activation in the liver. Despite this concept, the role of MLK 3 in modulating liver injury during nutrient excess has not been explored. Our aim was to determine if MLK 3 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 MLK 3 in mice is protective against HFHC diet‐induced NASH , in a weight‐independent fashion, through attenuation of JNK activation. MLK 3 is a potential therapeutic target for the treatment of human NASH .