Chinese Researchers Find a New Mechanism to Regulate Blood Cholesterol Level
Atherosclerotic cardiovascular disease (ASCVD) was one of the primary causes of mortality and morbidity in the world. Reducing plasma low density lipoprotein cholesterol (LDL-C) level can reduce the risk and the mortality of ASCVD. The level of LDL-C in the plasma is mainly regulated by low density lipoprotein receptor (LDLR). About 70% of LDL-C is cleared by endocytosis of LDLR in the liver. As LDLR plays a key role in the regulation of cholesterol homeostasis, hepatocytes regulates the LDLR level through a variety of signaling pathways. The transcriptional regulation of LDLR is mainly mediated by a feedback loop via cholesterol regulatory element binding protein (SREBP), while the post-transcriptional regulation is mainly mediated by proprotein convertase subtilisin/kexin type 9 (PCSK9). LDLR binds to its ligand LDL is then internalized into the cells, and recycles back to the plasma membrane.
However, in the presence of PCSK9, PCSK9 interacts with LDLR, thereby altering the molecular conformation of LDLR, making LDLR degraded directly through lysosome pathway and thus unable to return to the plasma membrane. Whether the interaction between LDLR and PCSK9 is regulated by other molecules is still unclear.
PhD candidate HUANG Meiqin and other researchers in Dr. CHEN Yan’s research group at Shanghai Institute of Nutrition and Health of Chinese Academy of Sciences, recently found that progesterone and adiponectin receptor 3 (PAQR3) play an important role in the regulation of cholesterol homeostasis. In the study, specific knockout of PAQR3 in the liver was found to reduce LDL-C and total cholesterol levels in the blood. Through a series of biochemical and cellular experiments, researchers found that PAQR3 can accelerate the degradation of LDLR by promoting the interaction between LDLR and PCSK9, and reduce the LDLR protein level in liver, thus affecting the cholesterol transport and clearance. This study reveals a new regulatory mechanism of the cholesterol level in vivo.
In view of the function of PAQR3 in regulating cholesterol homeostasis, this study provides a new way to reduce blood cholesterol levels in the future. For example, blocking the interaction of PAQR3 with LDLR or PCSK9 by small chemical molecules can lead to the separation of PCSK9 from LDLR, thereby increasing the recycling of LDLR of hepatocytes and lowering blood cholesterol levels.
This work was recently published in Metabolism with a title of "PAQR3 modulates blood cholesterol level by facilitating interaction between LDLR and PCSK9". The research was supported by the National Natural Science Foundation of China, the Ministry of Science and Technology of China, and the Chinese Academy of Sciences.
PAQR3 regulates LDLR-PCSK9 interaction (Image by Dr. Chen's Group)
WANG Jin (Ms.)
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences