Plasma LDL is produced from catabolism of VLDL and is cleared from circulation mainly via the hepatic LDL receptor (LDLR). Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes LDLR degradation, increasing plasma LDL cholesterol levels. Circulating PCSK9 is mainly secreted by the liver, while VLDL is exclusively secreted by hepatocytes. However, the mechanism regulating their secretion is not completely understood. Surfeit 4 (Surf4) is a cargo receptor localized in the ER membrane. It recruits cargos into COPII vesicles to facilitate their secretion. Here, we investigated the role of Surf4 in VLDL and PCSK9 secretion. We generated Surf4 liver-specific knockout (Surf4LKO) mice, and found that while knockout of Surf4 did not affect PCSK9 secretion, it significantly reduced plasma levels of cholesterol, triglyceride and lipid-binding protein apolipoprotein B (apoB). In cultured human hepatocytes, Surf4 co-immunoprecipitated and co-localized with apoB100, and Surf4 silencing reduced secretion of apoB100. Furthermore, knockdown of Surf4 in LDLR knockout (Ldlr-/-) mice significantly reduced triglyceride secretion, plasma levels of apoB and non-HDL cholesterol, and the development of atherosclerosis. However, Surf4LKO mice and Surf4 knockdown in Ldlr-/- mice displayed similar levels of liver lipids and plasma alanine aminotransferase activity as control mice, indicating that inhibition of Surf4 does not cause notable liver damage. Expression of stearoyl-CoA-1 (SCD1) was also reduced in the liver of these mice, suggesting a reduction in de novo lipogenesis. In summary, hepatic deficiency of Surf4 reduced VLDL secretion and the development of atherosclerosis, but did not cause hepatic lipid accumulation or liver damage.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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