Copine7 deficiency leads to hepatic fat accumulation via mitochondrial dysfunction.

OBJECTIVE

Mitochondrial dysfunction affects hepatic lipid homeostasis and promotes ROS generation. Copine7 (CPNE7) belongs to the ubiquitous copine family of calcium-dependent phospholipid binding proteins. CPNE7 has a high calcium ion binding affinity and the capacity to scavenge reactive oxygen species (ROS). A recent study reported that abnormalities in fatty acid and lipid metabolism were linked to the gene variant of CPNE7. Therefore, the purpose of this study is to examine the role of Cpne7 in hepatic lipid metabolism based on mitochondrial function.

METHODS

Lipid metabolism, mitochondrial function, and ROS production were investigated in high-fat diet (HFD)-fed mice and HO-damaged HepG2 hepatocytes following silencing or overexpression.

RESULTS

deficiency promoted severe hepatic steatosis in the HFD-induced NAFLD model. More importantly, mitochondrial dysfunction was observed along with an imbalance of mitochondrial dynamics in the livers of HFD-fed mice, resulting in high ROS levels. Similarly, -silenced HepG2 hepatocytes showed high ROS levels, mitochondrial dysfunction, and increased lipid contents. On the contrary, -overexpressed HepG2 cells showed low ROS levels, enhanced mitochondrial function and decreased lipid contents under HO-induced oxidative stress.

CONCLUSIONS

In the liver, deficiency causes excessive ROS formation and mitochondrial dysfunction, which aggravates lipid metabolism abnormalities. These findings provide evidence that deficiency contributes to the pathogenesis of NAFLD, suggesting as a novel therapeutic target for NAFLD.