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Lysophosphatidic acid signaling may initiate fetal hydrocephalus.

ABSTRACT: Fetal hydrocephalus (FH), characterized by the accumulation of cerebrospinal fluid, an enlarged head, and neurological dysfunction, is one of the most common neurological disorders of newborns. Although the etiology of FH remains unclear, it is associated with intracranial hemorrhage. Here, we report that lysophosphatidic acid (LPA), a blood-borne lipid that activates signaling through heterotrimeric guanosine 5'-triphosphate-binding protein (G protein)-coupled receptors, provides a molecular explanation for FH associated with hemorrhage. A mouse model of intracranial hemorrhage in which the brains of mouse embryos were exposed to blood or LPA resulted in development of FH. FH development was dependent on the expression of the LPA(1) receptor by neural progenitor cells. Administration of an LPA(1) receptor antagonist blocked development of FH. These findings implicate the LPA signaling pathway in the etiology of FH and suggest new potential targets for developing new treatments for FH.

SUBMITTER: Yung YC

PROVIDER: S-EPMC3653407 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Lysophosphatidic acid signaling may initiate fetal hydrocephalus.

Yung Yun C YC Mutoh Tetsuji T Lin Mu-En ME Noguchi Kyoko K Rivera Richard R RR Choi Ji Woong JW Kingsbury Marcy A MA Chun Jerold J

Science translational medicine 20110901 99

Fetal hydrocephalus (FH), characterized by the accumulation of cerebrospinal fluid, an enlarged head, and neurological dysfunction, is one of the most common neurological disorders of newborns. Although the etiology of FH remains unclear, it is associated with intracranial hemorrhage. Here, we report that lysophosphatidic acid (LPA), a blood-borne lipid that activates signaling through heterotrimeric guanosine 5'-triphosphate-binding protein (G protein)-coupled receptors, provides a molecular ex ...[more]

PMID: 21900594

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Project description:Liver cancer is one of the leading causes of death worldwide due to late diagnosis and scarcity of treatment options. The major risk factor for liver cancer is cirrhosis with the underlying causes of cirrhosis being viral infection (hepatitis B or C), metabolic deregulation (Non-alcoholic fatty liver disease (NAFLD) in the presence of obesity and diabetes), alcohol or cholestatic disorders. Lysophosphatidic acid (LPA) is a bioactive phospholipid with numerous effects, most of them compatible with the hallmarks of cancer (proliferation, migration, invasion, survival, evasion of apoptosis, deregulated metabolism, neoangiogenesis, etc.). Autotaxin (ATX) is the enzyme responsible for the bulk of extracellular LPA production, and together with LPA signaling is involved in chronic inflammatory diseases, fibrosis and cancer. This review discusses the most important findings and the mechanisms related to ATX/LPA/LPAR involvement on metabolic, viral and cholestatic liver disorders and their progression to liver cancer in the context of human patients and mouse models. It focuses on the role of ATX/LPA in NAFLD development and its progression to liver cancer as NAFLD has an increasing incidence which is associated with the increasing incidence of liver cancer. Bearing in mind that adipose tissue accounts for the largest amount of LPA production, many studies have implicated LPA in adipose tissue metabolism and inflammation, liver steatosis, insulin resistance, glucose intolerance and lipogenesis. At the same time, LPA and ATX play crucial roles in fibrotic diseases. Given that hepatocellular carcinoma (HCC) is usually developed on the background of liver fibrosis, therapies that both delay the progression of fibrosis and prevent its development to malignancy would be very promising. Therefore, ATX/LPA signaling appears as an attractive therapeutic target as evidenced by the fact that it is involved in both liver fibrosis progression and liver cancer development.

Project description:BACKGROUND:In the extracellular environment, lysophosphatidic acid (LPA) species are generated via autotaxin (ATX)-mediated hydrolysis of lysophospholipid precursors. Members of the LPA family are potent lipid mediators transmitting signals via six different G protein-coupled LPA receptors (LPAR1-6). The LPA signaling axis is indispensable for brain development and function of the nervous system; however, during damage of the central nervous system, LPA levels can increase and aberrant signaling events counteract brain function. Here, we investigated regulation of the ATX/LPA/LPAR axis in response to lipopolysaccharide-induced systemic inflammation in mice and potential neurotoxic polarization programs in LPA-activated primary murine microglia. METHODS:In vivo, LPAR1-6 expression was established by qPCR in whole murine brain homogenates and in FACS-sorted microglia. ELISAs were used to quantitate LPA concentrations in the brain and cyto-/chemokine secretion from primary microglia in vitro. Transcription factor phosphorylation was analyzed by immunoblotting, and plasma membrane markers were analyzed by flow cytometry. We used MAPK inhibitors to study signal integration by the JNK, p38, and ERK1/2 branches in response to LPA-mediated activation of primary microglia. RESULTS:Under acute and chronic inflammatory conditions, we observed a significant increase in LPA concentrations and differential regulation of LPAR, ATX (encoded by ENPP2), and cytosolic phospholipase A2 (encoded by PLA2G4A) gene expression in the brain and FACS-sorted microglia. During pathway analyses in vitro, the use of specific MAPK antagonists (SP600125, SB203580, and PD98059) revealed that JNK and p38 inhibition most efficiently attenuated LPA-induced phosphorylation of proinflammatory transcription factors (STAT1 and -3, p65, and c-Jun) and secretion of IL-6 and TNF?. All three inhibitors decreased LPA-mediated secretion of IL-1?, CXCL10, CXCL2, and CCL5. The plasma membrane marker CD40 was solely inhibited by SP600125 while all three inhibitors affected expression of CD86 and CD206. All MAPK antagonists reduced intracellular COX-2 and Arg1 as well as ROS and NO formation, and neurotoxicity of microglia-conditioned media. CONCLUSION:In the present study, we show that systemic inflammation induces aberrant ATX/LPA/LPAR homeostasis in the murine brain. LPA-mediated polarization of primary microglia via MAPK-dependent pathways induces features reminiscent of a neurotoxic phenotype.

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Lysophosphatidic acid signaling may initiate fetal hydrocephalus.

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Lysophosphatidic acid signaling may initiate fetal hydrocephalus.

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