LZP is required for hepatic triacylglycerol transportation through maintaining apolipoprotein B stability


Autoři: Jiao-Xiang Wu aff001;  Kun-Yan He aff002;  Zhuang-Zhuang Zhang aff001;  Yu-Lan Qu aff002;  Xian-Bin Su aff002;  Yi Shi aff002;  Na Wang aff002;  Lan Wang aff002;  Ze-Guang Han aff001
Působiště autorů: Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medici... aff001;  Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China aff002;  Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China aff003
Vyšlo v časopise: LZP is required for hepatic triacylglycerol transportation through maintaining apolipoprotein B stability. PLoS Genet 17(2): e1009357. doi:10.1371/journal.pgen.1009357
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009357

Souhrn

The conserved zona pellucida (ZP) domain is found in hundreds of extracellular proteins that are expressed in various organs and play a variety of roles as structural components, receptors and tumor suppressors. A liver-specific zona pellucida domain-containing protein (LZP), also named OIT3, has been shown to be mainly expressed in human and mouse hepatocytes; however, the physiological function of LZP in the liver remains unclear. Here, we show that Lzp deletion inhibited very low-density lipoprotein (VLDL) secretion, leading to hepatic TG accumulation and lower serum TG levels in mice. The apolipoprotein B (apoB) levels were significantly decreased in the liver, serum, and VLDL particles of LZP-deficient mice. In the presence of LZP, which is localized to the endoplasmic reticulum (ER) and Golgi apparatus, the ER-associated degradation (ERAD) of apoB was attenuated; in contrast, in the absence of LZP, apoB was ubiquitinated by AMFR, a known E3 ubiquitin ligase specific for apoB, and was subsequently degraded, leading to lower hepatic apoB levels and inhibited VLDL secretion. Interestingly, hepatic LZP levels were elevated in mice challenged with a high-fat diet and humans with simple hepatic steatosis, suggesting that LZP contributes to the physiological regulation of hepatic TG homeostasis. In general, our data establish an essential role for LZP in hepatic TG transportation and VLDL secretion by preventing the AMFR-mediated ubiquitination and degradation of apoB and therefore provide insight into the molecular function of LZP in hepatic lipid metabolism.

Klíčová slova:

Lipid metabolism – Fatty liver – Hepatocytes – Mouse models – Protein secretion – Secretion – Ubiquitination – Lipoprotein secretion


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