Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterol
- University of Michigan-Ann Arbor, United States
- Peking University, China
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 (Surf4fl/fl Alb-Cre+) to investigate the physiologic role of SURF4 in vivo. Surf4fl/fl Alb-Cre+ mice exhibited normal viability, gross development, and fertility. Plasma PCSK9 levels were reduced by ~60% in Surf4fl/fl Alb-Cre+ mice, with a corresponding ~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. Despite a small increase in liver mass and lipid content, histologic evaluation revealed no evidence of steatohepatitis or fibrosis in Surf4fl/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.
Data availability
Sequencing data have been deposited in GEO (accession number GSE214393) . All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for figure 1, figure 2, figure 3, and figure 6-figure supplement 1.
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Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterolNCBI Gene Expression Omnibus, GSE214393.
Article and author information
Author details
Funding
American Heart Association (20PRE35210706)
- Vi T Tang
University of Michigan (Rackham Predoctoral Fellowship)
- Vi T Tang
Howard Hughes Medical Institute
- David Ginsburg
National Institutes of Health (R35HL135793)
- David Ginsburg
National Institutes of Health (R01HL148333)
- Rami Khoriaty
National Institutes of Health (R01HL157062)
- Rami Khoriaty
National Institutes of Health (K08HL148552)
- Brian T Emmer
National Key Research and Development Program of China (2018YFA0506900)
- Xiao-Wei Chen
National Science Foundation of China (91954001)
- Xiao-Wei Chen
National Science Foundation of China (31571213)
- Xiao-Wei Chen
National Science Foundation of China (31521062)
- Xiao-Wei Chen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal care and use complied with the Principles of Laboratory and Animal Care established by the National Society for Medical Research. All animal protocols in this study have been approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Michigan (protocol number PRO00009304) and the IACUC of Peking University.
Copyright
© 2022, Tang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterol
eLife 11:e82269.
https://doi.org/10.7554/eLife.82269
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