期刊
ELIFE
卷 11, 期 -, 页码 -出版社
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.82269
关键词
secretion; SURF4; PCSK9; APOB; cholesterol
类别
资金
- NIH [R35HL135793, R01HL148333, R01HL157062, K08HL148552]
- National Key RD Program [2018YFA0506900]
- National Science Foundation of China [91957119, 91954001, 31571213, 31521062]
- American Heart Association Predoctoral Fellowship [20PRE35210706]
- University of Michigan Rackham Predoctoral Fellowship
This study reveals the importance of SURF4 in the hepatic secretion of PCSK9 and APOB-containing lipoproteins. By generating mice with hepatic SURF4 deficiency, the researchers found that the absence of SURF4 leads to a severe defect in lipoprotein secretion, resulting in decreased plasma cholesterol and triglyceride levels. These findings highlight the potential of SURF4 as a therapeutic target in atherosclerotic cardiovascular diseases.
PCSK9 negatively regulates low-density lipoprotein receptor (LDLR) abundance on the cell surface, leading to decreased hepatic clearance of LDL particles and increased levels of plasma cholesterol. We previously identified SURF4 as a cargo receptor that facilitates PCSK9 secretion in HEK293T cells (Emmer et al., 2018). Here, we generated hepatic SURF4-deficient mice (Surf4(fl/fl) Alb-Cre(+)) to investigate the physiologic role of SURF4 in vivo. Surf4(fl/fl)Alb-Cre(+) mice exhibited normal viability, gross development, and fertility. Plasma PCSK9 levels were reduced by similar to 60% in Surf4(fl/fl) Alb-Cre(+) mice, with a corresponding similar to 50% increase in steady state LDLR protein abundance in the liver, consistent with SURF4 functioning as a cargo receptor for PCSK9. Surprisingly, these mice exhibited a marked reduction in plasma cholesterol and triglyceride levels out of proportion to the partial increase in hepatic LDLR abundance. Detailed characterization of lipoprotein metabolism in these mice instead revealed a severe defect in hepatic lipoprotein secretion, consistent with prior reports of SURF4 also promoting the secretion of apolipoprotein B (APOB). Despite a small increase in liver mass and lipid content, histologic evaluation revealed no evidence of steatohepatitis or fibrosis in Surf4(fl/fl) Alb-Cre(+) mice. Acute depletion of hepatic SURF4 by CRISPR/Cas9 or liver-targeted siRNA in adult mice confirms these findings. Together, these data support the physiologic significance of SURF4 in the hepatic secretion of PCSK9 and APOB-containing lipoproteins and its potential as a therapeutic target in atherosclerotic cardiovascular diseases.
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