Title | Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterol |
Authors | Tang, Vi T. McCormick, Joseph Xu, Bolin Wang, Yawei Fang, Huan Wang, Xiao Siemieniak, David Khoriaty, Rami Emmer, Brian T. Chen, Xiao-Wei Ginsburg, David |
Affiliation | Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA Univ Michigan, Life Sci Inst, Ann Arbor, MI 48109 USA Peking Univ, Coll Future Technol, Beijing, Peoples R China Peking Univ, Ctr Life Sci, Beijing, Peoples R China Peking Univ, State Key Lab Membrane Biol, Beijing, Peoples R China Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA Univ Michigan, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA |
Keywords | MICE LIPOPROTEINS RECEPTOR DRIVEN PCSK9 |
Issue Date | 4-Oct-2022 |
Publisher | ELIFE |
Abstract | 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. |
URI | http://hdl.handle.net/20.500.11897/671368 |
ISSN | 2050-084X |
DOI | 10.7554/eLife.82269 |
Indexed | SCI(E) |
Appears in Collections: | 生命科学学院 其他实验室 膜生物学国家重点实验室 |