The Circadian Clock controls Hepatic Inflammation in MASLD

Area of Science:

• Chronobiology
• Hepatology
• Immunology

Background:

• The circadian clock regulates liver homeostasis, and its disruption is linked to metabolic disorders.
• The role of circadian misalignment in the progression of Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) to Metabolic dysfunction-Associated Steatohepatitis (MASH) is unclear.

Purpose of the Study:

• To investigate the circadian clock's role in MASH development and hepatic inflammation.
• To dissect the specific contribution of the immune clock to MASH progression.

Main Methods:

• Used environmental models of circadian misalignment and a high-fat, high-sucrose, cholesterol-enriched (HFHSC) diet.
• Employed metabolic, immune, single nuclei transcriptomic, and lipidomic profiling.
• Utilized genetic models with myeloid-specific Rev-erbα overexpression.

Main Results:

• Circadian misalignment exacerbated hepatic inflammation, characterized by increased pro-inflammatory genes and immune cell infiltration, including hepatic lipid-associated macrophages (hLAMs).
• This inflammation promoted fibrotic deposition, but circadian misalignment did not worsen glucose intolerance or hepatic steatosis.
• Myeloid-specific Rev-erbα overexpression attenuated hepatic inflammation in mice on an HFHSC diet.

Conclusions:

• The circadian clock influences hepatic fatty acid profiles and inflammation.
• Circadian misalignment aggravates MASLD by increasing liver inflammation and fibrosis.
• Targeting myeloid Rev-erbα may be a therapeutic strategy for liver inflammation in MASLD.