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Non-Necroptotic Roles of MLKL in Diet-Induced Obesity, Liver Pathology, and Insulin Sensitivity: Insights from a
Phoebe Ohene-Marfo1, Hoang Van M Nguyen2, Sabira Mohammed3
1Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Abstract:
Chronic inflammation is a key player in metabolic dysfunction-associated fatty liver disease (MAFLD) progression. Necroptosis, an inflammatory cell death pathway, is elevated in MAFLD patients and mouse models, yet its role is unclear due to the diverse mouse models and inhibition strategies. In our study, we inhibited necroptosis by targeting mixed lineage kinase domain-like pseudokinase (MLKL), the terminal effector of necroptosis, in a high-fat, high-fructose, high-cholesterol (HFHFrHC) mouse model of diet-induced MAFLD. Despite the HFHFrHC diet upregulating MLKL (2.5-fold), WT mice livers showed no increase in necroptosis markers or associated proinflammatory cytokines. Surprisingly, Mlkl mice experienced exacerbated liver inflammation without protection from diet-induced liver damage, steatosis, or fibrosis. In contrast, Mlkl mice showed a significant reduction in these parameters that was associated with elevated Pparα and Pparγ levels. Both Mlkl and Mlkl mice on the HFHFrHC diet resisted diet-induced obesity, attributed to the increased beiging, enhanced oxygen consumption, and energy expenditure due to adipose tissue, and exhibited improved insulin sensitivity. These findings highlight the tissue-specific effects of MLKL on the liver and adipose tissue, and they suggest a dose-dependent effect of MLKL on liver pathology.
Insights
Targeting mixed lineage kinase domain-like pseudokinase (MLKL) in fatty liver disease surprisingly worsened liver inflammation in mice. MLKL inhibition protected against diet-induced obesity and improved insulin sensitivity, revealing tissue-specific roles.
Area of Science:
- Hepatology
- Immunology
- Metabolic disease research
Background:
- Chronic inflammation drives metabolic dysfunction-associated fatty liver disease (MAFLD) progression.
- Necroptosis, an inflammatory cell death pathway, is implicated in MAFLD, but its precise role remains unclear.
- Mixed lineage kinase domain-like pseudokinase (MLKL) is the terminal effector of necroptosis.
Purpose of the Study:
- To investigate the role of MLKL-mediated necroptosis in diet-induced MAFLD.
- To determine the effects of MLKL inhibition on liver pathology and metabolic parameters in a mouse model.
Main Methods:
- Utilized a high-fat, high-fructose, high-cholesterol (HFHFrHC) diet mouse model of MAFLD.
- Employed wild-type (WT) mice and mice lacking MLKL (Mlkl-/-).
- Assessed liver inflammation, steatosis, fibrosis, necroptosis markers, and metabolic parameters including obesity and insulin sensitivity.
Main Results:
- HFHFrHC diet upregulated MLKL in WT mice livers, but necroptosis markers and proinflammatory cytokines did not increase.
- Mlkl-/- mice exhibited exacerbated liver inflammation and no protection against diet-induced liver damage, steatosis, or fibrosis.
- Mlkl-/- mice showed reduced liver damage, steatosis, and fibrosis, associated with elevated Pparα and Pparγ.
- Both WT and Mlkl-/- mice resisted diet-induced obesity, with Mlkl-/- mice showing increased adipose tissue beiging, oxygen consumption, and energy expenditure, alongside improved insulin sensitivity.
Conclusions:
- MLKL exhibits tissue-specific effects, promoting liver inflammation while potentially suppressing protective metabolic adaptations in adipose tissue.
- MLKL inhibition paradoxically exacerbates liver inflammation in this MAFLD model.
- MLKL deficiency confers protection against diet-induced obesity and improves insulin sensitivity, suggesting a complex, dose-dependent role in MAFLD pathogenesis.
