Mixed lineage kinase 3 deficient mice are protected against the high fat high carbohydrate diet-induced steatohepatitis

Samar C Ibrahim, Gregory James Gores, Petra Hirsova, Michelle Kirby, Lili Miles, Anja Jaeschke, Rohit Kohli

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 C57BL/6J mice, and wild type (WT) mice C57BL/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.

Original languageEnglish (US)
Pages (from-to)427-437
Number of pages11
JournalLiver International
Volume34
Issue number3
DOIs
StatePublished - Mar 2014

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High Fat Diet
Fatty Liver
Carbohydrates
Liver
Phosphotransferases
Inbred C57BL Mouse
MAP Kinase Kinase Kinases
mitogen-activated protein kinase kinase kinase 11
Wounds and Injuries
Weight Gain
Hepatocytes
Triglycerides
Fats
Phosphorylation
Apoptosis
Diet
Inflammation
Weights and Measures
Food
Non-alcoholic Fatty Liver Disease

Keywords

  • Fibrosis
  • Inflammation
  • JNK
  • Lipoapoptosis
  • Nonalcoholic fatty liver disease

ASJC Scopus subject areas

  • Hepatology

Cite this

Mixed lineage kinase 3 deficient mice are protected against the high fat high carbohydrate diet-induced steatohepatitis. / Ibrahim, Samar C; Gores, Gregory James; Hirsova, Petra; Kirby, Michelle; Miles, Lili; Jaeschke, Anja; Kohli, Rohit.

In: Liver International, Vol. 34, No. 3, 03.2014, p. 427-437.

Research output: Contribution to journalArticle

Ibrahim, Samar C ; Gores, Gregory James ; Hirsova, Petra ; Kirby, Michelle ; Miles, Lili ; Jaeschke, Anja ; Kohli, Rohit. / Mixed lineage kinase 3 deficient mice are protected against the high fat high carbohydrate diet-induced steatohepatitis. In: Liver International. 2014 ; Vol. 34, No. 3. pp. 427-437.
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AU - Ibrahim, Samar C

AU - Gores, Gregory James

AU - Hirsova, Petra

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AU - Miles, Lili

AU - Jaeschke, Anja

AU - Kohli, Rohit

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N2 - 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 C57BL/6J mice, and wild type (WT) mice C57BL/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.

AB - 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 C57BL/6J mice, and wild type (WT) mice C57BL/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.

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KW - Lipoapoptosis

KW - Nonalcoholic fatty liver disease

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