Atherosclerosis-associated hepatic secretion of VLDL but not PCSK9 is dependent on cargo receptor protein Surf4
| العنوان: | Atherosclerosis-associated hepatic secretion of VLDL but not PCSK9 is dependent on cargo receptor protein Surf4 |
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| المؤلفون: | Yishi Shen, Shucun Qin, Bingxiang Wang, Yongfang Zhao, Lei Zhai, Boyan Liu, Xiaole Chang, Adekunle Alabi, Shijun Deng, Maggie Wang, Hong-mei Gu, Da-Wei Zhang, Xiao-dan Xia, Guiqing Wang, Sijie Xing |
| المصدر: | Journal of Lipid Research Journal of Lipid Research, Vol 62, Iss, Pp 100091-(2021) |
| بيانات النشر: | American Society for Biochemistry and Molecular Biology, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Alb, albumin, Very low-density lipoprotein, Apolipoprotein B, TANGO1, Transport and Golgi Organization 1, 030204 cardiovascular system & hematology, Lipoproteins, VLDL, Biochemistry, Microsomal triglyceride transfer protein, apoB100, chemistry.chemical_compound, Mice, 0302 clinical medicine, Endocrinology, AAV, adeno-associated virus, stearyl-CoA-1, lipid metabolism, COPII, classical coat protein complex II, Cells, Cultured, lipoprotein metabolism, Mice, Knockout, apoB, apolipoprotein B, biology, CE, cholesteryl ester, TG, triglyceride, LDLR, LDL receptor, Surf4, Surfeit 4, MTP, microsomal triglyceride transfer protein, Lipogenesis, Cholesteryl ester, lipids (amino acids, peptides, and proteins), ASCVD, atherosclerotic cardiovascular disease, Proprotein Convertase 9, Research Article, medicine.medical_specialty, apoB100, apolipoprotein B100, QD415-436, liver, LDL, 03 medical and health sciences, Internal medicine, ALT, alanine aminotransferase, medicine, Animals, Secretion, triglyceride, Cholesterol, Surf4LKO, Surf4 liver-specific knockout, nutritional and metabolic diseases, Membrane Proteins, SCD1, stearoyl-CoA desaturase-1, Cell Biology, Atherosclerosis, TC, total cholesterol, Mice, Inbred C57BL, 030104 developmental biology, LDLR, chemistry, Receptors, LDL, LDL receptor, biology.protein, VTV, VLDL transport vesicle, apolipoproteins, PCSK9, proprotein convertase subtilisin/kexin type 9 |
| الوصف: | Plasma LDL is produced from catabolism of VLDL and cleared from circulation mainly via the hepatic LDL receptor (LDLR). Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes LDLR degradation, increasing plasma LDL-C levels. Circulating PCSK9 is mainly secreted by the liver, whereas 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 coat protein complex II vesicles to facilitate their secretion. Here, we investigated the role of Surf4 in VLDL and PCSK9 secretion. We generated Surf4 liver-specific knockout mice and found that knockout of Surf4 did not affect PCSK9 secretion, whereas it significantly reduced plasma levels of cholesterol, triglyceride, and lipid-binding protein apolipoprotein B (apoB). In cultured human hepatocytes, Surf4 coimmunoprecipitated and colocalized with apolipoprotein B100, and Surf4 silencing reduced secretion of apolipoprotein B100. Furthermore, knockdown of Surf4 in LDLR knockout (Ldlr−/−) mice significantly reduced triglyceride secretion, plasma levels of apoB and non-HDL-C, and the development of atherosclerosis. However, Surf4 liver-specific knockout 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 desaturase-1 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 significant hepatic lipid accumulation or liver damage. |
| اللغة: | English |
| تدمد: | 1539-7262 0022-2275 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3ace96902105c8bd0f6e5ca427b95574Test http://europepmc.org/articles/PMC8261665Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....3ace96902105c8bd0f6e5ca427b95574 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15397262 00222275 |
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