Department of Molecular and Integrative Physiology, University of Michigan-Ann Arbor, Ann Arbor, United States; Life Sciences Institute, University of Michigan-Ann Arbor, Ann Arbor, United States
Joseph McCormick
Life Sciences Institute, University of Michigan-Ann Arbor, Ann Arbor, United States
Bolin Xu
College of Future Technology, Peking University, Beijing, China
Yawei Wang
Center for Life Sciences, Peking University, Beijing, China
Huan Fang
College of Future Technology, Peking University, Beijing, China
Xiao Wang
College of Future Technology, Peking University, Beijing, China; State Key Laboratory of Membrane Biology, Peking University, Beijing, China
David Siemieniak
Life Sciences Institute, University of Michigan-Ann Arbor, Ann Arbor, United States; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States
Rami Khoriaty
Department of Internal Medicine, University of Michigan-Ann Arbor, Ann Arbor, United States; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United States
Life Sciences Institute, University of Michigan-Ann Arbor, Ann Arbor, United States; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, United States; Department of Internal Medicine, University of Michigan-Ann Arbor, Ann Arbor, United States; Department of Human Genetics, University of Michigan, Ann Arbor, United States; Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, United States
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 (APOB). 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.
