Loss of metabolic adaptation in lean MAFLD is driven by endotoxemia leading to epigenetic reprogramming

Area of Science:

• Hepatology
• Immunology
• Metabolic Syndrome

Background:

• Lean patients with metabolic-associated fatty liver disease (MAFLD) exhibit an initial adaptive metabolic response involving increased serum bile acids and Farnesoid X Receptor (FXR) activity.
• The mechanisms by which this adaptive response fails, leading to adverse outcomes comparable to obese MAFLD patients, remain unclear.

Purpose of the Study:

• To investigate the mechanisms underlying the failure of adaptive metabolic responses in lean MAFLD patients.
• To explore the role of macrophage inflammatory responses and epigenetic alterations in lean MAFLD.
• To identify potential therapeutic targets for restoring metabolic adaptation in lean MAFLD.

Main Methods:

• Comparative analysis of serum bile acids and FXR activity in lean MAFLD patients versus healthy controls.
• Assessment of endotoxemia and macrophage inflammatory cytokine production in response to Toll-like receptor (TLR) ligand activation.
• Epigenomic profiling of macrophages from lean MAFLD patients to identify alterations in signaling pathways.

Main Results:

• Lean MAFLD patients exhibit endotoxemia and heightened inflammatory cytokine production by macrophages upon TLR activation compared to healthy subjects.
• Epigenomic alterations in lean MAFLD macrophages suppress bile acid signaling, promoting inflammation.
• These findings highlight a shift from adaptive to maladaptive responses in lean MAFLD.

Conclusions:

• The maladaptive inflammatory response in lean MAFLD is driven by macrophage epigenomic changes that impair bile acid signaling.
• Selective restoration of bile acid signaling presents a potential therapeutic strategy to reinstate adaptive metabolic responses in lean MAFLD patients.