A novel regulatory mechanism for starvation-induced ketone body production was discovered

Recently, Molecular Metabolism published a research paper on THE CHEN Yan Research Group of the Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences entitled PAQR9 regulates hepatic ketogenesis and fatty acid oxidation during fasting by modulating protein stability of PPARα. The study was the first to find that the endoplasmic reticulo protein PAQR9 can participate in hunger-induced liver ketone production and fatty acid oxidation by regulating the stability of the transcription factor PPARα in liver cells.

The alternation of hunger and eating is a fundamental physiological process of life, in which a large number of metabolic state changes can occur. The liver is an important metabolic organ in the body, and in the process of starvation, it responds to the signal of nutrient deficiency, carries out fatty acid oxidation and ketone body production, and provides energy to the body. This process is regulated by transcription factors, where PPARα is the core transcription factor and deletion of the PPARα gene leads to reduced fatty acid oxidation during starvation. Previous research by the research group has found that PPARα is degraded by the ubiquitination modification of the E3 ubiquitin ligase HUWE1 mediate proteasome pathway.

Recently, Lin Yijun, a doctoral student in the research group, found through big data analysis and animal experiments that PAQR9 is one of the most significant downregulation genes in the liver under starvation, and identified that the expression of PAQR9 during hunger-eating is directly regulated by PPARγ. Through a series of metabolic characterization studies in PAQR9 knockout mice, it was found that knockout PAQR9 did not affect the metabolic state of mice under normal eating conditions, but significantly reduced the ketone production and fatty acid oxidation capacity of the liver under starvation. Molecular mechanism studies have found that when PPARα is knocked out of the liver of mice, transcriptional levels are not affected, but protein content is significantly reduced. Cell experiments have confirmed that PAQR9 is able to reduce degradation caused by Ubiquitination of PPARα. Further study of the regulatory mechanism of PAQR9 on the level of PPARα ubiquitination found that PAQR9 can be competitively bound to HUWE1, which mediates PPARα degradation, to protect PPARα from degradation. Both HUWE1 knockout in vitro and in vivo PPARα agonist replenishment experiments fully verified the reliability of PAQR9 competitively binding HUWE1 to protect PPARα protein stability model. In summary, the study revealed that the endoplasmic reticulo protein PAQR9 can regulate the activity of the transcription factor PPARα through ubiquitination, revealing a new regulatory mechanism for lipid metabolism in the liver.

The research work is supported by the National Natural Science Foundation of China and the Ministry of Science and Technology, as well as the Public Technology Platform and the Animal Platform of the Institute of Nutrition and Health.

PAQR9 competitively binds to HUWE1 to protect PPARα protein stability

Source: Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences