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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. Author summary: The metabolic diseases, such as obesity, atherosclerosis, and nonalcoholic fatty liver disease (NAFLD), are often characterized by increased triacylglycerol (TG) and cholesterol levels. TG is synthesized mainly in the liver, incorporated into Very Low-Density Lipoproteins (VLDLs), and then secreted into blood. During TG metabolism, apolipoprotein B (apoB) is necessary for the assembly and secretion of TG-rich VLDLs because it functions as the major component of VLDLs. In the present work, using a genetically engineered mouse model, we discovered that the liver-specific zona pellucida domain-containing protein (LZP)-deficient mice exhibit hepatic TG accumulation and low blood TG, which are eventually ascribed to the decrease of apoB protein. In physiological condition, the unnecessary apoB is usually ubiquitinated by E3 ligase AMFR, and subsequently degraded by ubiquitination proteasomes. Significantly, LZP can interact with apoB, and prevent the AMFR-mediated apoB degradation. Therefore, LZP deficiency destroys the protection for apoB, leading to the enhancement of apoB ubiquitination and degradation, and the secondary decrease of TG-rich VLDL secretion, which finally results in TG accumulation in liver and lower blood TG. This study reveals a novel regulator of TG-rich VLDL assembly and secretion, which could advance our knowledge on lipid metabolism. [ABSTRACT FROM AUTHOR]