Lipid phosphate phosphohydrolase type 1 (LPP1) degrades extracellular lysophosphatidic acid in vivo.
LPA (lysophosphatidic acid) is a lipid mediator that stimulates cell proliferation and growth, and is involved in physiological and pathological processes such as wound healing, platelet activation, angiogenesis and the growth of tumours. Therefore defining the mechanisms of LPA production and degradation are of interest in understanding the regulation of these processes. Extracellular LPA synthesis is relatively well understood, whereas the mechanisms of its degradation are not. One route of LPA degradation is dephosphorylation. A candidate enzyme is the integral membrane exophosphatase LPP1 (lipid phosphate phosphohydrolase type 1). In the present paper, we report the development of a mouse wherein the LPP1 gene (Ppap2a) was disrupted. The homozygous mice, which are phenotypically unremarkable, generally lack Ppap2a mRNA, and multiple tissues exhibit a substantial (35-95%) reduction in LPA phosphatase activity. Compared with wild-type littermates, Ppap2a(tr/tr) animals have increased levels of plasma LPA, and LPA injected intravenously is metabolized at a 4-fold lower rate. Our results demonstrate that LPA is rapidly metabolized in the bloodstream and that LPP1 is an important determinant of this turnover. These results indicate that LPP1 is a catabolic enzyme for LPA in vivo.
Tomsig
Jose L
JL
Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, U.S.A.
Snyder
Ashley H
AH
Berdyshev
Evgeny V
EV
Skobeleva
Anastasia
A
Mataya
Chifundo
C
Natarajan
Viswanathan
V
Brindley
David N
DN
Lynch
Kevin R
KR
D000818:Animals; D001483:Base Sequence; D005110:Extracellular Space / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D008246:Lysophospholipids / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009928:Organ Specificity; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D008246:Lysophospholipids; D012333:RNA, Messenger; C112948:lipid phosphate phosphatase; D010711:Phosphatidate Phosphatase; C032881:lysophosphatidic acid