Nuclear factor interleukin 3 and metabolic dysfunction-associated fatty liver disease development

Area of Science:

• Metabolic disease research
• Hepatology
• Immunology

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health concern.
• The role of Nfil3 in diet-induced liver disease and gut microbiota alterations is not fully understood.
• Sex-specific responses to metabolic challenges require further investigation.

Purpose of the Study:

• To investigate the sex-specific effects of Nfil3 deficiency on high-fat diet (HFD)-induced MASLD.
• To evaluate the impact of Nfil3 on gut microbiota (GM) composition and bile acid (BA) profiles.
• To explore the therapeutic potential of Nfil3 inhibition in MASLD.

Main Methods:

• Induction of MASLD in wild-type and Nfil3-deficient (NKO) mice using a high-fat diet (HFD).
• Evaluation of hepatic immune response via flow cytometry.
• Analysis of gut microbiota diversity and bile acid profiles.
• Assessment of gene and protein expression related to inflammation and gut barrier function.

Main Results:

• NKO mice exhibited reduced body weight, serum triglycerides, liver injury, inflammation, and fat accumulation compared to controls.
• Nfil3 deletion decreased macrophage infiltration in fibrotic liver tissues and suppressed proinflammatory markers.
• GM alpha diversity was increased in NKO mice across sexes, and BA profiles were significantly altered.
• Nfil3 deficiency modulated the Nfil3-FXR-FGF15 axis, impacting bile acid recycling.

Conclusions:

• Nfil3 plays a significant role in the pathogenesis of HFD-induced MASLD.
• Nfil3 deficiency confers protection against MASLD by modulating immune responses, gut microbiota, and bile acid metabolism.
• Targeting Nfil3 represents a promising therapeutic strategy for MASLD treatment.