Decrease in fat de novo synthesis and chemokine ligand expression in non-alcoholic fatty liver disease caused by
Waqar Khalid Saeed1, Dae Won Jun1,2, Kiseok Jang3
1Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South Korea.
Background And Aim:
Receptor-interacting serine/threonine kinase 3 and mixed lineage kinase domain-like pseudokinase (MLKL) have gained attention as apoptosis alternate cell death signaling molecules. We aimed to evaluate the role of MLKL in non-alcoholic fatty liver disease (NAFLD).
Methods:
Hepatic tissue MLKL expression was compared between NAFLD patients and healthy controls. High-fat diet was fed to wild-type and MLKL-knockout (KO) mice for 12 weeks. Brown adipose fat tissue was measured by [18 F]-fluorodeoxyglucose positron emission tomography. Energy expenditure was measured by indirect calorimetry. Anti-MLKL effects were also evaluated in in vitro setting using U937 and HepG2 cells.
Results:
Hepatic tissue MLKL expression increased in NAFLD patients compared with healthy controls. MLKL expression increased according to the degree of steatosis, ballooning, and inflammation. High-fat diet-fed MLKL-KO mice displayed decreased alanine aminotransferase, triglycerides, liver weight, NAFLD activity score (6.3 vs 3.5, P < 0.001), steatosis score (3.0 vs 1.8, P < 0.001), inflammation, and ballooning degeneration compared with wild-type mice. SREBP1c, fatty acid synthase, and SCD-1 expressions decreased in MLKL-KO mice. Adipose tissue F4/80-positive crown-like structures were also reduced in MLKL-KO mice. HepG2 cells treated with necrosulfonamide (an MLKL inhibitor) showed reduced Nile red staining and reduced SREBP1c and SCD-1 expressions. Stimulation of necroptosis using lipopolysaccharide + caspase inhibitor (zVAD) increased CXCL1/2 expressions in U937 monocyte cells. Lipopolysaccharide + zVAD-induced increased expressions of CXCL1/2 were reduced with necrosulfonamide treatment.
Conclusions:
Mixed lineage kinase domain-like pseudokinase inhibition has protective effects in non-alcoholic steatohepatitis by decreasing hepatic de novo fat synthesis and chemokine (C-X-C motif) ligand expressions.
Insights
Mixed lineage kinase domain-like pseudokinase (MLKL) inhibition shows promise for treating non-alcoholic steatohepatitis (NASH). Targeting MLKL reduces liver fat accumulation and inflammation, offering a potential therapeutic strategy for NAFLD.
Area of Science:
- Cellular signaling pathways
- Molecular mechanisms of cell death
- Hepatology and metabolic diseases
Background:
- Receptor-interacting serine/threonine kinase 3 and mixed lineage kinase domain-like pseudokinase (MLKL) are implicated in alternative cell death pathways.
- Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern with complex pathogenesis.
- The specific role of MLKL in NAFLD progression requires further elucidation.
Purpose of the Study:
- To investigate the role of MLKL in the development and progression of NAFLD.
- To assess the therapeutic potential of targeting MLKL in NAFLD models.
Main Methods:
- Comparative analysis of hepatic MLKL expression in NAFLD patients versus healthy controls.
- In vivo studies using high-fat diet-induced NAFLD in wild-type and MLKL-knockout mice.
- In vitro experiments utilizing HepG2 and U937 cell lines to evaluate MLKL inhibition effects.
Main Results:
- Hepatic MLKL expression was significantly elevated in NAFLD patients, correlating with disease severity.
- MLKL-knockout mice exhibited reduced liver injury markers, steatosis, inflammation, and de novo lipogenesis compared to wild-type controls.
- Inhibition of MLKL in cell models decreased fat accumulation and inflammatory mediator expression.
Conclusions:
- MLKL plays a critical role in the pathogenesis of NAFLD, particularly in non-alcoholic steatohepatitis (NASH).
- Targeting MLKL demonstrates protective effects by reducing hepatic fat synthesis and associated inflammatory responses.
- MLKL inhibition represents a potential therapeutic strategy for managing NASH.
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