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

Abstract

Background 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. Aims 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 to WT mice. In addition, compared to 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.

Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis

“…1) (6). LPC can activate proapoptotic signaling akin to palmitate (6,16), and lead to extracellular vesicle (EV) release (24). Palmitatederived C16:0 ceramide is associated with insulin resistance and steatohepatitis (25,26), and at a cellular level can induce EV release (27).…”

“…Lipid-induced activation of mixed lineage kinase 3 (MLK3) and c-Jun N-terminal kinase (JNK) (24,32), and the ER stress response (36,37) are key cellular pathways that mediate proapoptotic signaling initiated by toxic saturated free fatty acids and in the steatotic liver (38). Sphingolipids, too, are elevated in NASH (25), and C16:0 ceramide has recently been linked to the pathophysiology of NASH (39); therefore, we discuss these pathways and concepts below.…”

Loss of TRB3 Alters Dynamics of MLK3-JNK Signaling and Inhibits Cytokine-activated Pancreatic Beta Cell Death

“…Accumulating evidence suggests that the MLK-JNK signaling pathway induces inflammation of metabolic tissues and contributes to impaired glucose homeostasis and decreased insulin sensitivity (33)(34)(35)(36)(37)(38). In the beta cell, cross-talk between MLK-JNK and insulin-AKT signaling determines the balance between dysfunction/death and survival, highlighting the importance of mechanisms that can fine tune and tip the balance toward JNK or AKT activity.…”

Mixed-lineage kinase 3 pharmacological inhibition attenuates murine nonalcoholic steatohepatitis

“…We have reported previously that MLK3 -/-mice are protected against liver injury, fibrosis, and inflammation in a murine model of NASH-inducing diet (22,23). We also demonstrated that hepatocytes under lipotoxic stress release chemotactic extracellular vesicles (EVs) by an MLK3-dependent mechanism (23); these vesicles are enriched with the potent macrophage chemotactic ligand (C-X-C motif) ligand 10 (CXCL10), expression of which is regulated by MLK3 in hepatocytes (11).…”

“…Bolstered by our data supporting MLK3 as a crucial proinflammatory and proapoptotic mediator in our preclinical in vitro and in vivo model of NASH (22,23), we elected to test the protective effect of the MLK3 pharmacological inhibitor URMC099 in our murine model of diet-induced NASH and obesity. URMC099 is a selective small-molecule MLK3 pharmacological inhibitor that was developed for human use.…”