Copine7 deficiency leads to hepatic fat accumulation via mitochondrial dysfunction

Area of Science:

• Biochemistry
• Cell Biology
• Hepatology

Background:

• Mitochondrial dysfunction impacts hepatic lipid homeostasis and reactive oxygen species (ROS) generation.
• Copine7 (CPNE7), a calcium-dependent phospholipid-binding protein, possesses ROS scavenging capacity.
• Gene variants of CPNE7 are linked to fatty acid and lipid metabolism abnormalities.

Purpose of the Study:

• To investigate the role of Copine7 (CPNE7) in hepatic lipid metabolism.
• To elucidate the relationship between CPNE7, mitochondrial function, and ROS production in the liver.

Main Methods:

• Utilized high-fat diet (HFD)-fed Cpne7 knockout (^-/-) mice.
• Employed H₂O₂-damaged HepG2 hepatocytes with CPNE7 silencing or overexpression.
• Assessed lipid metabolism, mitochondrial function, and ROS production.

Main Results:

• Cpne7 deficiency exacerbated hepatic steatosis in HFD-induced NAFLD models.
• Mice lacking Cpne7 exhibited mitochondrial dysfunction, imbalanced mitochondrial dynamics, and elevated ROS.
• CPNE7-silenced hepatocytes showed increased ROS, mitochondrial dysfunction, and lipid accumulation.
• CPNE7 overexpression in hepatocytes reduced ROS, improved mitochondrial function, and decreased lipid content under oxidative stress.

Conclusions:

• Cpne7 deficiency promotes ROS generation and mitochondrial dysfunction, worsening hepatic lipid metabolism abnormalities.
• Cpne7 deficiency contributes to the pathogenesis of non-alcoholic fatty liver disease (NAFLD).
• CPNE7 emerges as a potential novel therapeutic target for NAFLD.