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J. Biol. Chem., Vol. 282, Issue 18, 13726-13735, May 4, 2007

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A Host Lipase Detoxifies Bacterial Lipopolysaccharides in the Liver and Spleen^*

Baomei Shao, Mingfang Lu, Steven C. Katz, Alan W. Varley, John Hardwick, Thomas E. Rogers^¶, Noredia Ojogun, Donald C. Rockey, Ronald P. DeMatteo, and Robert S. Munford^||1

From the Departments of Internal Medicine, ^||Microbiology and ^¶Pathology, University of Texas Southwestern Medical School, Dallas, Texas 75390-9113 and the Hepatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Much of the inflammatory response of the body to bloodborne Gram-negative bacteria occurs in the liver and spleen, the major organs that remove these bacteria and their lipopolysaccharide (LPS, endotoxin) from the bloodstream. We show here that LPS undergoes deacylation in the liver and spleen by acyloxyacyl hydrolase (AOAH), an endogenous lipase that selectively removes the secondary fatty acyl chains that are required for LPS recognition by its mammalian signaling receptor, MD-2-TLR4. We further show that Kupffer cells produce AOAH and are required for hepatic LPS deacylation in vivo. AOAH-deficient mice did not deacylate LPS and, whereas their inflammatory responses to low doses of LPS were similar to those of wild type mice for 3 days after LPS challenge, they subsequently developed pronounced hepatosplenomegaly. Providing recombinant AOAH restored LPS deacylating ability to Aoah^-/- mice and prevented LPS-induced hepatomegaly. AOAH-mediated deacylation is a previously unappreciated mechanism that prevents prolonged inflammatory reactions to Gram-negative bacteria and LPS in the liver and spleen.

Received for publication, October 6, 2006 , and in revised form, January 26, 2007.

^* This work was supported by National Institutes of Health Grants AI18188 and DK068346 and by the Jan and Henri Bromberg Chair in Internal Medicine, University of Texas Southwestern Medical School. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental methods and a supplemental table.

¹ To whom correspondence should be addressed: University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9113. Tel.: 214-648-3480; Fax: 214-648-9478; E-mail: Robert.munford{at}utsouthwestern.edu.

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