Xiuyun Wang1,2,3, Min Guo4, Qian Wang1,2,3, Qingjie Wang1,2,3, Shasha Zuo1,2,3, Xu Zhang1,2,3, Hui Tong1,2,3, Jizheng Chen5, Huimin Wang6, Xiaowei Chen6, Junyuan Guo7, Xiong Su7, Hui Liang8, Hongwen Zhou1,9, John Zhong Li1,2,3. 1. The Key Laboratory of Rare Metabolic Disease, Nanjing Medical University, Nanjing, China. 2. Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. 3. The Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China. 4. The State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China. 5. The State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China. 6. The Sate Key laboratory of Membrane Biology, Center for Life Science and Institute of Molecular Medicine, Peking University, Beijing, China. 7. Department of Biochemistry and Molecular Biology, Soochow University Medical College, Suzhou, China. 8. Department of General Surgery, The First affiliated Hospital of Nanjing Medical University, Nanjing, China. 9. Department of Endocrinology, The First affiliated Hospital of Nanjing Medical University, Nanjing, China.
Abstract
BACKGROUND AND AIMS: The regulation of hepatic very-low-density lipoprotein (VLDL) secretion is vital for lipid metabolism whose pathogenetic status is involved in fatty liver disease and dyslipidemia seen in hepatic steatosis. Accumulated evidence suggest that apolipoprotein E (ApoE) is closely related to hepatic VLDL secretion. Here, we report that the expression of patatin-like phospholipase domain containing protein 7 (PNPLA7) is strongly induced by hepatic steatosis and positively correlates with plasma triacylglycerol (TAG) levels in the human subjects, whereas the role of PNPLA7 in hepatic VLDL secretion is unknown. APPROACH AND RESULTS: Herein, with genetic manipulation in the mice, the deficiency of hepatic PNPLA7 expression resulted in reduced VLDL secretion accompanied by enhanced hepatic lipid accumulation and decreased hepatic ApoE expression. Furthermore, knockdown of PNPLA7 in the livers of the db/db mice also resulted in significant reduction in plasma TAG level but aggravated hepatic steatosis. Importantly, we observed that PNPLA7 interacted with ApoE and presumably at the site of endoplasmic reticulum. Mechanistically, we have shown that PNPLA7 could modulate polyubiquitination and proteasomal-mediated degradation of ApoE. Overexpressed ApoE restored the impaired VLDL-TAG metabolism in PNPLA7-knockdown primary hepatocytes. CONCLUSION: PNPLA7 plays a critical role in regulating hepatic VLDL secretion by modulating ApoE stability through its interaction with ApoE.
BACKGROUND AND AIMS: The regulation of hepatic very-low-density lipoprotein (VLDL) secretion is vital for lipid metabolism whose pathogenetic status is involved in fatty liver disease and dyslipidemia seen in hepatic steatosis. Accumulated evidence suggest that apolipoprotein E (ApoE) is closely related to hepatic VLDL secretion. Here, we report that the expression of patatin-like phospholipase domain containing protein 7 (PNPLA7) is strongly induced by hepatic steatosis and positively correlates with plasma triacylglycerol (TAG) levels in the human subjects, whereas the role of PNPLA7 in hepatic VLDL secretion is unknown. APPROACH AND RESULTS: Herein, with genetic manipulation in the mice, the deficiency of hepaticPNPLA7 expression resulted in reduced VLDL secretion accompanied by enhanced hepatic lipid accumulation and decreased hepatic ApoE expression. Furthermore, knockdown of PNPLA7 in the livers of the db/db mice also resulted in significant reduction in plasma TAG level but aggravated hepatic steatosis. Importantly, we observed that PNPLA7 interacted with ApoE and presumably at the site of endoplasmic reticulum. Mechanistically, we have shown that PNPLA7 could modulate polyubiquitination and proteasomal-mediated degradation of ApoE. Overexpressed ApoE restored the impaired VLDL-TAG metabolism in PNPLA7-knockdown primary hepatocytes. CONCLUSION:PNPLA7 plays a critical role in regulating hepatic VLDL secretion by modulating ApoE stability through its interaction with ApoE.