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.
pan class="Chemical">LPA (pan class="Chemical">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.
Authors: Yutong Zhao; Satish K Kalari; Peter V Usatyuk; Irina Gorshkova; Donghong He; Tonya Watkins; David N Brindley; Chaode Sun; Robert Bittman; Joe G N Garcia; Evgeni V Berdyshev; Viswanathan Natarajan Journal: J Biol Chem Date: 2007-03-22 Impact factor: 5.157
Authors: Harald M H G Albers; Anping Dong; Laurens A van Meeteren; David A Egan; Manjula Sunkara; Erica W van Tilburg; Karianne Schuurman; Olaf van Tellingen; Andrew J Morris; Susan S Smyth; Wouter H Moolenaar; Huib Ovaa Journal: Proc Natl Acad Sci U S A Date: 2010-04-01 Impact factor: 11.205