Integrin β3 Orchestrates Hepatic Steatosis via a Novel CD36-Dependent Lipid Uptake Complex

Area of Science:

• Hepatology
• Molecular Biology
• Metabolic Diseases

Background:

• Metabolic dysfunction-related steatohepatitis (MASH) involves hepatic fibrosis and lipid accumulation.
• The role of Integrin beta 3 (ITGB3) in regulating hepatic lipid metabolism and its mechanisms in MASH are not fully understood.

Purpose of the Study:

• To investigate the direct role of ITGB3 in hepatic lipid metabolism and its underlying mechanisms in MASH.
• To explore ITGB3 as a potential therapeutic target for MASH.

Main Methods:

• Transcriptomic analysis in human and murine MASH models.
• Hepatocyte-specific overexpression and deletion of ITGB3 in mice.
• Investigation of the ITGB3/DHHC5/CD36 signaling pathway.
• Pharmacologic inhibition of ITGB3.

Main Results:

• ITGB3 is upregulated in hepatocytes during MASH and exacerbates obesity, insulin resistance, steatosis, and fibrosis in mice.
• ITGB3 enhances CD36-mediated fatty acid uptake by modulating LYN stability and promoting DHHC5 activity.
• ITGB3/DHHC5/CD36 complex formation enhances CD36 palmitoylation and fatty acid uptake.
• ITGB3 deficiency alleviates MASH phenotypes, while DHHC5 overexpression rescues these in ITGB3-deficient mice.
• Pharmacologic inhibition of ITGB3 improved lipid profiles and hepatic steatosis.

Conclusions:

• ITGB3 directly drives hepatic steatosis in MASH through a novel mechanism involving CD36-mediated fatty acid uptake.
• Targeting ITGB3 to modulate CD36 activity presents a potential therapeutic strategy for MASH.