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J. Biol. Chem., Vol. 279, Issue 7, 6171-6181, February 13, 2004

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Maturation of Hepatic Lipase

FORMATION OF FUNCTIONAL ENZYME IN THE ENDOPLASMIC RETICULUM IS THE RATE-LIMITING STEP IN ITS SECRETION^*

Osnat Ben-Zeev and Mark H. Doolittle

From the Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073 and the Department of Medicine, UCLA, Los Angeles, California 90095

Among three lipases in the lipase gene family, hepatic lipase (HL), lipoprotein lipase, and pancreatic lipase, HL exhibits the lowest intracellular specific activity (i.e. minimal amounts of catalytic activity accompanied by massive amounts of inactive lipase mass in the endoplasmic reticulum (ER)). In addition, HL has a distinctive sedimentation profile, where the inactive mass overlaps the region containing active dimeric HL and trails into progressively larger molecular forms. Eventually, at least half of the HL inactive mass in the ER reaches an active, dimeric conformation (t = 2 h) and is rapidly secreted. The remaining inactive mass is degraded. HL maturation occurs in the ER and is strongly dependent on binding to calnexin in the early co-/post-translational stages. Later stages of HL maturation occur without calnexin assistance, although inactive HL at all stages appears to be associated in distinct complexes with other ER proteins. Thus, unlike other lipases in the gene family, HL maturation is the rate-limiting step in its secretion as a functional enzyme.

Received for publication, September 10, 2003 , and in revised form, October 24, 2003.

^* This work was supported by National Institutes of Health Grant HL28481 and the Department of Veterans Affairs. 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.

To whom correspondence should be addressed: VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Bldg. 113, Rm. 312, Los Angeles, CA 90073. E-mail: markdool{at}ucla.edu.

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