Heparan sulfate dissociates serum amyloid A (SAA) from acute-phase high-density lipoprotein, promoting SAA aggregation.
Inflammation-related (AA) amyloidosis is a severe clinical disorder characterized by the systemic deposition of the acute-phase reactant serum amyloid A (SAA). SAA is normally associated with the high-density lipoprotein (HDL) fraction in plasma, but under yet unclear circumstances, the apolipoprotein is converted into amyloid fibrils. AA amyloid and heparan sulfate (HS) display an intimate relationship in situ, suggesting a role for HS in the pathogenic process. This study reports that HS dissociates SAA from HDLs isolated from inflamed mouse plasma. Application of surface plasmon resonance spectroscopy and molecular modeling suggests that HS simultaneously binds to two apolipoproteins of HDL, SAA and ApoA-I, and thereby induce SAA dissociation. The activity requires a minimum chain length of 12-14 sugar units, proposing an explanation to previous findings that short HS fragments preclude AA amyloidosis. The results address the initial events in the pathogenesis of AA amyloidosis.
Department of Medical Biochemistry and Microbiology, The Biomedical Center, Husargatan 3, Box 582, Uppsala University, 751 23 Uppsala, Sweden.
Fredrik
F
Noborn
John B
JB
Ancsin
Wimal
W
Ubhayasekera
Robert
R
Kisilevsky
Jin-Ping
JP
Li
D000686:Amyloidosis / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D000685:Serum Amyloid A Protein / Q000737:chemistry / Q000378:metabolism; D020349:Surface Plasmon Resonance
D016632:Apolipoprotein A-I; D006497:Heparan Sulfate; D008075:Lipoproteins, HDL; D000685:Serum Amyloid A Protein