Promoting export of macrophage cholesterol: the physiological role of a major acute-phase protein, serum amyloid A 2.1.
We show that murine macrophages that have ingested cell membranes as a source of cholesterol exhibit a marked increase in acyl-CoA:cholesterol acyl transferase (ACAT) activity. Exposure of these macrophages to acute-phase high-density lipoprotein (HDL) results in a marked reduction of ACAT and enhancement of cholesteryl ester hydrolase (CEH) activities, phenomena not seen with native HDL. These complementary but opposite effects of acute-phase HDL on the two enzyme systems that regulate the balance between esterified (storage) cholesterol and unesterified (transportable) cholesterol are shown to reside with serum amyloid A (SAA) 2.1, an acute-phase apolipoprotein of HDL whose plasma concentration increases 500- to 1,000-fold within 24 h of acute tissue injury. Mild trypsin treatment of acute-phase HDL almost completely abolishes the apolipoprotein-mediated effects on the cholesteryl ester cycle in cholesterol-laden macrophages. The physiological effect of SAA2.1 on macrophage cholesterol is to shift it into a transportable state enhancing its rate of export, which we confirm in tissue culture and in vivo. The export process is shown to be coupled to the ATP binding cassette transport system. Our findings integrate previous isolated observations about SAA into the sphere of cholesterol transport, establish a function for a major acute-phase protein, and offer a novel approach to mobilizing macrophage cholesterol at sites of atherogenesis.
Tam
Shui Pang
SP
Department of Biochemistry, Queen's University, Kingston, Ontario, Canada K7L 3N6.
Flexman
Alana
A
Hulme
Jennifer
J
Kisilevsky
Robert
R
D000595:Amino Acid Sequence; D000818:Animals; D001053:Apolipoproteins / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000201:enzymology; D008081:Liposomes / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D000685:Serum Amyloid A Protein / Q000737:chemistry / Q000378:metabolism*; D002787:Sterol Esterase / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000378:metabolism; D013997:Time Factors
D001053:Apolipoproteins; D008076:Cholesterol, HDL; D008081:Liposomes; D000685:Serum Amyloid A Protein; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; D002787:Sterol Esterase