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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:539.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

ApoE-Dependent Modulation of HDL and Atherosclerosis by G2A in LDL Receptor–Deficient Mice Independent of Bone Marrow–Derived Cells

Brian W. Parks; Roshni Srivastava; Shaohua Yu; Janusz H.S. Kabarowski

From the Department of Microbiology, University of Alabama at Birmingham.

Correspondence to Janusz H.S. Kabarowski, Department of Microbiology, University of Alabama at Birmingham, BBRB 334, 845 19th Street South, Birmingham AL 35294-2170. E-mail janusz{at}uab.edu

Objective— Deletion of the lysophospholipid-sensitive receptor, G2A, in low-density lipoprotein receptor knockout (LDLR^–/–) mice elevates plasma high-density lipoprotein (HDL) cholesterol and suppresses atherosclerosis. However, chemotactic action of G2A in monocytes/macrophages, in addition to its modulatory effect on HDL, may contribute to the proatherogenic action of G2A.

Methods and Results— We determined that deletion of G2A in LDLR^–/– mice increases the ApoA1, ApoE, and cholesterol content of plasma HDL fractions. Hepatocytes were shown to express G2A and hepatocytes from G2A-deficient LDLR^–/– mice secreted more ApoA1 and ApoE in HDL fractions compared to their G2A-sufficient counterparts. The atheroprotective and HDL modulatory effects of G2A deficiency were dependent on the presence of ApoE, as deletion of G2A in ApoE^–/– and ApoE^–/–LDLR^–/– mice failed to raise HDL and did not suppress atherosclerosis. G2A deficiency in bone marrow–derived cells of LDLR^–/– mice had no effect on atherosclerosis or HDL, whereas G2A deficiency in resident tissues was sufficient to raise HDL and suppress atherosclerosis.

Conclusion— These data demonstrate that the chemotactic function of G2A in bone marrow–derived monocytes does not modulate atherosclerosis in LDLR^–/– mice and suggest an ApoE-dependent function for G2A in the control of hepatic HDL metabolism that might contribute to its proatherogenic action.

G2A promotes atherosclerosis in LDLR knockout mice. Atheroprotection in G2A-deficient LDLR knockout mice was dependent on ApoE and associated with HDL elevation and increased hepatocyte ApoA1 secretion. G2A deficiency in resident tissues, not bone marrow-derived cells, elevated HDL and suppressed atherosclerosis. Modulation of HDL might contribute to G2A proatherogenic action.

Key Words: G2A • atherosclerosis • high-density lipoprotein • ApoE • bone marrow • hepatocytes