Summary
The brain is composed of many lipids with varied forms that serve not only as structural components but also as essential signaling molecules. Lysophosphatidic acid (LPA) is an important bioactive lipid species that is part of the lysophospholipid (LP) family. LPA is primarily derived from membrane phospholipids and signals through six cognate G protein-coupled receptors (GPCRs), LPA1-6. These receptors are expressed on most cell types within central and peripheral nervous tissues and have been functionally linked to many neural processes and pathways. This review covers a current understanding of LPA signaling in the nervous system, with particular focus on the relevance of LPA to both physiological and diseased states.
In the original Supplemental Information for this Article, the time of treatment with tamoxifen given in Figure S3 was P1, but the actual time of treatment was P21. This has now been corrected in the Supplemental Information online.
Lysophosphatidic acid (LPA) is a signaling lipid that binds to six known lysophosphatidic acid receptors (LPARs), named LPA1-LPA6. These receptors initiate signaling cascades relevant to development, maintenance, and healing processes throughout the body. The diversity and specificity of LPA signaling, especially in relation to cancer and autoimmune disorders, makes LPA receptor modulation an attractive target for drug development. Several LPAR-specific analogues and small molecules have been synthesized and are efficacious in attenuating pathology in disease models. To date, at least three compounds have passed phase I and phase II clinical trials for idiopathic pulmonary fibrosis and systemic sclerosis. This review focuses on the promising therapeutic directions emerging in LPA signaling toward ameliorating several diseases, including cancer, fibrosis, arthritis, hydrocephalus, and traumatic injury.
Objective
Chylomicron and very low-density lipoprotein remnants are cleared from the circulation in the liver by heparan sulfate proteoglycan (HSPG) receptors (syndecan-1), the low-density lipoprotein receptor (LDLR), and LDLR-related protein-1 (LRP1), but the relative contribution of each class of receptors under different dietary conditions remains unclear.
Approach and Results
Triglyceride-rich lipoprotein clearance was measured in AlbCre+Ndst1f/f, Ldlr−/−, and AlbCre+Lrp1f/f mice and mice containing combinations of these mutations. Triglyceride measurements in single and double mutant mice showed that HSPGs and LDLR dominate clearance under fasting conditions and postprandial conditions, but LRP1 contributes significantly when LDLR is absent. Mice lacking hepatic expression of all three receptors (AlbCre+Ndst1f/f
Lrp1f/f
Ldlr−/−) displayed dramatic hyperlipidemia (870 ± 270 mg triglyceride/dL; 1300 ± 350 mg of total cholesterol/dL) and exhibited persistent elevated postprandial triglyceride levels due to reduced hepatic clearance. Analysis of the particles accumulating in mutants showed that HSPGs preferentially clear a subset of small triglyceride-rich lipoproteins (~20-40 nm diameter), while LDLR and LRP1 clear larger particles (~40-60 nm diameter). Finally, we show that HSPGs play a major role in clearance of TRLs in mice fed normal chow or under postprandial conditions but appear to play a less significant role on a high fat diet.
Conclusion
These data show that HSPGs, LDLR, and LRP1 clear distinct subsets of particles, that HSPGs work independently from LDLR and LRP1, and that HSPGs, LDLR, and LRP1 are the three major hepatic TRL clearance receptors in mice.
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