A Plasma Protein Network Regulates PM20D1 and N-Acyl Amino Acid Bioactivity

Joon T Kim; Mark P Jedrychowski; Wei Wei; Daniel Fernandez; Curt R Fischer; Steven M Banik; Bruce M Spiegelman; Jonathan Z Long

doi:10.1016/j.chembiol.2020.04.009

A Plasma Protein Network Regulates PM20D1 and N-Acyl Amino Acid Bioactivity

Cell Chem Biol. 2020 Sep 17;27(9):1130-1139.e4. doi: 10.1016/j.chembiol.2020.04.009. Epub 2020 May 12.

Authors

Joon T Kim¹, Mark P Jedrychowski², Wei Wei³, Daniel Fernandez⁴, Curt R Fischer⁴, Steven M Banik⁵, Bruce M Spiegelman², Jonathan Z Long⁶

Affiliations

¹ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA.
² Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
³ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA.
⁴ Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA.
⁵ Department of Chemistry, Stanford University, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA.
⁶ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA. Electronic address: jzlong@stanford.edu.

Abstract

N-acyl amino acids are a family of cold-inducible circulating lipids that stimulate thermogenesis. Their biosynthesis is mediated by a secreted enzyme called PM20D1. The extracellular mechanisms that regulate PM20D1 or N-acyl amino acid activity in the complex environment of blood plasma remains unknown. Using quantitative proteomics, here we show that PM20D1 circulates in tight association with both low- and high-density lipoproteins. Lipoprotein particles are powerful co-activators of PM20D1 activity in vitro and N-acyl amino acid biosynthesis in vivo. We also identify serum albumin as a physiologic N-acyl amino acid carrier, which spatially segregates N-acyl amino acids away from their sites of production, confers resistance to hydrolytic degradation, and establishes an equilibrium between thermogenic "free" versus inactive "bound" fractions. These data establish lipoprotein particles as principal extracellular sites of N-acyl amino acid biosynthesis and identify a lipoprotein-albumin network that regulates the activity of a circulating thermogenic lipid family.

Keywords: APOE; Alzheimer; HDL; LDL; N-acyl amino acid; PM20D1; circulating; lipids; lipoprotein; obesity; plasma.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue, Brown / cytology
Adipose Tissue, Brown / metabolism
Adipose Tissue, White / cytology
Adipose Tissue, White / metabolism
Amidohydrolases / genetics
Amidohydrolases / metabolism*
Amino Acids / blood
Amino Acids / chemistry
Amino Acids / metabolism*
Animals
Apolipoproteins E / deficiency
Apolipoproteins E / genetics
Arachidonic Acids / blood
Arachidonic Acids / chemistry
Arachidonic Acids / metabolism
Blood Proteins / chemistry
Blood Proteins / metabolism*
Cell Line
Glycine / analogs & derivatives
Glycine / blood
Glycine / chemistry
Glycine / metabolism
Humans
Lipoproteins / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Protein Binding
Proteomics
Serum Albumin / chemistry
Serum Albumin / metabolism

Substances

Amino Acids
Apoe protein, mouse
Apolipoproteins E
Arachidonic Acids
Blood Proteins
Lipoproteins
N-arachidonylglycine
Serum Albumin
Amidohydrolases
PM20D1 protein, human
Glycine

Abstract

Publication types

MeSH terms

Substances

Grants and funding