Asprosin-FABP5 Interaction Modulates Mitochondrial Fatty Acid Oxidation through PPARα Contributing to MASLD...

Area of Science:

• Hepatology
• Metabolic Diseases
• Molecular Biology

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) involves complex liver metabolic alterations.
• Asprosin, a fasting-released hormone, targets the liver, but its role in MASLD is unclear.

Purpose of the Study:

• To investigate the role of asprosin in MASLD pathogenesis.
• To explore asprosin as a potential biomarker and therapeutic target for MASLD.

Main Methods:

• Measured plasma asprosin levels in MASLD patients and animal models.
• Utilized hepatocyte-specific asprosin overexpression and knockdown models in mice.
• Investigated molecular mechanisms involving FABP5, PPARα, and fatty acid oxidation (FAO).
• Assessed therapeutic potential of GalNAc-siRNAs targeting FABP5.

Main Results:

• Plasma asprosin levels and hepatic asprosin expression are elevated in MASLD.
• Hepatocyte asprosin overexpression impairs hepatic FAO; knockdown enhances FAO and improves MASLD treatment outcomes.
• Asprosin interacts with FABP5, leading to abnormal nuclear localization and inhibition of PPARα transcriptional activity, disrupting hepatic FAO.
• Targeting hepatic FABP5 with GalNAc-siRNAs ameliorates hepatic steatosis.

Conclusions:

• Elevated asprosin is implicated in MASLD pathogenesis by disrupting hepatic FAO.
• Asprosin serves as a potential biomarker for MASLD diagnosis and prognosis.
• Inhibiting hepatic asprosin or FABP5 presents promising therapeutic strategies for MASLD.