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Signalling by lysophosphatidate and its health implications
Denise G Hemmings1,2,3,4, David N Brindley3,5
1Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, Canada.
Essays in Biochemistry
|May 27, 2020
Summary
Lysophosphatidic acid (LPA) signaling, regulated by autotaxin (ATX) and lipid phosphate phosphatases (LPP), drives inflammation and disease. Targeting this pathway offers novel therapeutic strategies for inflammatory conditions.
Area of Science:
- Biochemistry
- Cell Biology
- Pathology
Background:
- Extracellular lysophosphatidic acid (LPA) signaling is crucial for cellular functions like proliferation, migration, survival, and angiogenesis.
- This signaling pathway is tightly regulated by the balance between LPA production by autotaxin (ATX) and its degradation by lipid phosphate phosphatases (LPPs).
- Dysregulated LPA signaling, particularly when inflammation becomes chronic, contributes to various pathological conditions including arthritis, pain, obesity, cancer, fibrosis, and cardiovascular disease.
Purpose of the Study:
- To elucidate the role of LPA signaling in the development and progression of inflammatory diseases.
- To investigate the mechanisms by which LPA signaling contributes to maladaptive processes such as fibrosis and metastasis.
- To explore the potential of targeting LPA signaling as a therapeutic strategy for inflammatory and related conditions.
Main Methods:
- Analysis of the regulatory balance between autotaxin (ATX) and lipid phosphate phosphatases (LPPs) in LPA formation and degradation.
- Examination of the expression levels of G-protein-coupled LPA receptors and their role in cellular responses.
- Investigation of LPA signaling in the context of tissue damage, inflammation, wound healing, and disease models (e.g., arthritis, cancer, fibrosis).
Main Results:
- Acute inflammation stimulates ATX production and LPA signaling, contributing to wound healing.
- Chronic, unresolved inflammation leads to maladaptive LPA signaling, promoting conditions like arthritis, pain, obesity, cancer, and fibrosis.
- LPA signaling promotes tumor metastasis and confers resistance to chemotherapy and radiotherapy; dexamethasone attenuates radiation-induced fibrosis by reducing ATX and LPA receptor expression and increasing LPA degradation.
Conclusions:
- Dysregulated LPA signaling is a key driver of chronic inflammation and underlies numerous significant medical conditions.
- LPA signaling contributes to fibrosis, metastasis, and treatment resistance in cancer.
- Modulating LPA signaling, for instance, by using agents like dexamethasone, presents a promising therapeutic avenue for treating a wide range of inflammatory diseases.
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