GPIHBP1 on oligodendrocytes binds lipoprotein lipase within the human brain
Abstract
In peripheral tissues, lipoprotein lipase (LPL) is secreted by parenchymal cells (adipocytes, myocytes) into the interstitial spaces, where it is captured by GPIHBP1 (a glycosylphosphatidylinositol-anchored protein of capillary endothelial cells) and escorted to the luminal surface of capillaries. The LPL inside capillaries hydrolyzes glycerolipids in the plasma lipoproteins, releasing fatty acids for parenchymal cells. In the central nervous system, LPL is synthesized by multiple cell types [e.g., microglia, oligodendrocyte precursor cells (OPCs)] and secreted into the interstitium, but a binding site for the LPL has never been identified. By examining single nuclei RNA-seq databases of the human brain, we found that GPIHBP1 is expressed by oligodendrocytes but not by OPCs. This gene-expression profile (high in oligodendrocytes, low in OPCs) is also observed in genes for myelin structural proteins, fatty acid binding and transport proteins, and lipid biosynthetic enzymes. GPIHBP1 expression in oligodendrocytes was confirmed by in situ hybridization studies of human brain and by immunohistochemical staining. Of note, GPIHBP1 and LPL are colocalized on oligodendrocytes in the human brain. Our findings identify GPIHBP1 as a principal binding site for interstitial LPL in the human brain and suggest that GPIHBP1-bound LPL could hydrolyze interstitial lipids and thereby supply oligodendrocytes with fatty acid nutrients.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Minjun Liu
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
Madison Hung
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
Ellen Kozlov
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
Megan Hung
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
Mariana Colaço-Gaspar
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
Shristi Roy
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
Yiping Tu
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
Shino D. Magaki
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles
Christopher K. Williams
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles
Maarja Andaloussi Mäe
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University
Erik C. B. Johnson
Department of Neurology, Emory University
Robert W. Siegel
Laboratory for Experimental Medicine, Lilly Research Laboratories, Eli Lilly and Company
Robert J. Konrad
Lilly Research Laboratories, Eli Lilly and Company
Michael Ploug
Finsen Laboratory, Copenhagen University Hospital - Rigshospitalet
Christer Betsholtz
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University
Anne P. Beigneux
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
Liqun He
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University
Loren G. Fong
Department of Medicine, David Geffen School of Medicine, University of California Los Angeles
Stephen G. Young
Department of Medicine, David Geffen School of Medicine, University of California Los Angeles