Ursodeoxycholyl lysophosphatidylethanolamide protects against hepatic ischemia/reperfusion injury via phospholipid metabolism-mediated mitochondrial quality control.

Abstract

Mitochondrial dysfunction is the leading cause of reactive oxygen species (ROS) burst and apoptosis in hepatic ischemia/reperfusion (I/R) injury. Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a hepatotargeted agent that exerts hepatoprotective roles by regulating lipid metabolism. Our previous studies have shown that UDCA-LPE improves hepatic I/R injury by inhibiting apoptosis and inflammation. However, the role of UDCA-LPE in lipid metabolism and mitochondrial function in hepatic I/R remains unknown. In the present study, we investigated the role of UDCA-LPE in hepatic I/R by focusing on the interface of phospholipid metabolism and mitochondrial homeostasis. Livers from 28-week-old mice, primary hepatocytes and HepG2 cells were subjected to in vivo and in vitro I/R, respectively. Analyses of oxidative stress, imaging, ATP generation, genetics, and lipidomics showed that I/R was associated with mitochondrial dysfunction and a reduction in phospholipids. UDCA-LPE alleviated mitochondria-dependent oxidative stress and apoptosis and prevented the decrease of phospholipid levels. Our study found that cytosolic phospholipase A2 (cPLA2 ), a phospholipase that is activated during I/R, hydrolyzed mitochondrial membrane phospholipids and led to mitochondria-mediated oxidative stress and apoptosis. UDCA-LPE inhibited the interaction between cPLA2 and mitochondria and reduced phospholipid hydrolysis-mediated injury. UDCA-LPE might regulate the crosstalk between the phospholipid metabolism and the mitochondria, restore mitochondrial function and ameliorate I/R injury.

• Authors: Jian Gu, Tao Zhang, Jianrong Guo, Ke Chen, Guobin Wang, Huili Li, Jiliang Wang
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 34 Issue 5 Pg. 6198-6214 (05 2020) ISSN: 1530-6860 [Electronic] United States
• PMID: 32162746 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. The FASEB Journal published by Wiley Periodicals, Inc. on behalf of Federation of American Societies for Experimental Biology.

Chemical References

• Lysophospholipids
• Phospholipids
• Protective Agents
• Reactive Oxygen Species
• ursodeoxycholyl lysophosphatidylethanolamide
• Ursodeoxycholic Acid

Topics

• Animals
• Apoptosis
• Hep G2 Cells
• Hepatocytes (cytology, drug effects, metabolism)
• Humans
• Lipid Metabolism Disorders (etiology, metabolism, prevention & control)
• Liver Diseases (etiology, metabolism, prevention & control)
• Lysophospholipids (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Mitochondria (drug effects, metabolism, pathology)
• Oxidative Stress (drug effects)
• Phospholipids (metabolism)
• Protective Agents (pharmacology)
• Reactive Oxygen Species
• Reperfusion Injury (complications)
• Ursodeoxycholic Acid (analogs & derivatives, pharmacology)