Heparan sulfate dissociates serum amyloid A (SAA) from acute-phase high-density lipoprotein, promoting SAA aggregation

Department of Medical Biochemistry and Microbiology, The Biomedical Center, Husargatan 3, Box 582, Uppsala University, 751 23 Uppsala, Sweden.
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2012; 287(30):25669-77. DOI: 10.1074/jbc.M112.363895
Source: PubMed

ABSTRACT 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.

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    • "SAA synthesized in the local lung microenvironment may also generate HDL free aggregates, which unlike HDL bound SAA promotes inflammatory cytokine production through activation of PRRs such as ALX/FPR2. Furthermore, extracellular matrix products such as heparan sulfate fragments have recently been shown to promote dissociation of SAA bound to HDLs under acidic conditions (Noborn et al., 2012). Intriguingly, cigarette smoke exposure causes increased shedding and fragmentation of heparan sulfate (Yao et al., 2010), which may further facilitate the formation of active SAA aggregates in the lung. "
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