Role of sphingosine 1-phosphate and lysophosphatidic acid in fibrosis

Pyne, Nigel J.; Dubois, Gerald; Pyne, Susan

doi:10.1016/j.bbalip.2012.07.003

Cited by 59 publications

(54 citation statements)

References 136 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, plasma lysophosphatidylcholine levels are reduced in obesity and Type 2 diabetes [31] and a recent study specifically identified circulating lysophosphatidylcholine levels as markers of metabolically benign non-alcoholic fatty liver [32]. Lysophospholipids are also of great interest as studies have demonstrated their functional roles beyond membrane structure and function, including impairment of insulin signalling independent of ceramide and DAG, increase in VLDL (very-low-density lipoprotein) assembly and secretion, fibrosis and inflammation [30,33,34]. Phospholipases and lysophosphatidylcholine acyltransferase, enzymes that co-ordinate the regulation of lysolipid levels, have been shown to moderate hepatic lipotoxicity, insulin resistance and fibrosis [30,35,36].…”

Section: Discussionmentioning

confidence: 99%

Metabolomic profiling in liver of adiponectin-knockout mice uncovers lysophospholipid metabolism as an important target of adiponectin action

Liu

Sen

Wannaiampikul

et al. 2015

Biochemical Journal

View full text Add to dashboard Cite

Adiponectin mediates anti-diabetic effects via increasing hepatic insulin sensitivity and direct metabolic effects. In the present study, we conducted a comprehensive and unbiased metabolomic profiling of liver tissue from AdKO (adiponectin-knockout) mice, with and without adiponectin supplementation, fed on an HFD (high-fat diet) to derive insight into the mechanisms and consequences of insulin resistance. Hepatic lipid accumulation and insulin resistance induced by the HFD were reduced by adiponectin. The HFD significantly altered levels of 147 metabolites, and bioinformatic analysis indicated that one of the most striking changes was the profile of increased lysophospholipids. These changes were largely corrected by adiponectin, at least in part via direct regulation of PLA2 (phospholipase A2) as palmitate-induced PLA2 activation was attenuated by adiponectin in primary hepatocytes. Notable decreases in several glycerolipids after the HFD were reversed by adiponectin, which also corrected elevations in several diacyglycerol and ceramide species. Our data also indicate that stimulation of ω-oxidation of fatty acids by the HFD is enhanced by adiponectin. In conclusion, this metabolomic profiling approach in AdKO mice identified important targets of adiponectin action, including PLA2, to regulate lysophospholipid metabolism and ω-oxidation of fatty acids.

show abstract

Section: Discussionmentioning

confidence: 99%

Metabolomic profiling in liver of adiponectin-knockout mice uncovers lysophospholipid metabolism as an important target of adiponectin action

Liu

Sen

Wannaiampikul

et al. 2015

Biochemical Journal

View full text Add to dashboard Cite

show abstract

“…Lysophosphatidic acid (LPA), a small bioactive phospholipid, regulates several cellular processes via binding to and activating its high-affinity G proteincoupled receptors. LPA exerts a wide range of cellular responses, such as cell proliferation and transformation [2]. LPA is synthesized by activated platelets, rendering it a prominent mediator of tissue injury and wound healing responses [3].…”

Section: Introductionmentioning

confidence: 99%

Regulation of silicosis formation by lysophosphatidic acid and its receptors

Chen

Mao

Zhang

et al. 2014

Experimental Lung Research

View full text Add to dashboard Cite

Silicosis is a serious occupational disease characterized by lung fibrosis that is caused by long-term inhalation of silica-containing fine particles. Lysophosphatidic acid (LPA) and LPA1/3 plays a role in lung fibrosis. Until recently, there has been little research investigating the role of LPA and LPA receptors (LPAR) in silica-induced development of pulmonary fibrosis. In this study, we evaluated the hypothesis that LPA and LPA1/3 may play a role in silicosis pathogenesis using rat silicosis models induced by intratracheal instillation of silica, and randomly divided into control, silica, and VPC-12249 groups. LPA serum and bronchoalveolar lavage fluid (BALF) levels were quantified by ELISA. α-smooth muscle actin (α-SMA), type I and III collagen protein expression was quantified by western blotting (WB), and type I and III collagen mRNAs detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Lung hydroxyproline (HYP) levels were detected using alkaline hydrolysis, with hematoxylin and eosin (H&E) and picrosirius red staining used for pathological examination. In vitro experiments showed that LPA stimulated fibroblasts proliferated in a time and dose-dependent manner and promoted expression of α-SMA, and type I and III collagen. Moreover, LPA serum and BALF levels increased in silica-instilled rats. In vivo and in vitro experiments revealed that α-SMA expression and collagen deposition reduced significantly after VPC-12249 treatment, and histopathological results show VPC-12249 alleviates silicosis progression. In conclusion, our findings suggest that LPA promotes the proliferation, transformation, and collagen synthesis of fibroblasts, and that LPA-LPA1/3 are involved in the development of silicosis and may serve as novel therapeutic targets for treatment.

show abstract

“…Several antagonists of LPA and specific inhibitors and antibodies of LPA receptors are being explored for therapeutic importance in the treatment of different medical conditions, including cancer and fibrosis. 93 Extracellular LPA is produced predominantly by ATX, a secretory LysoPLD that is ubiquitously expressed. 52 Autotaxin/lysophospholipase D. ATX was originally discovered as an autocrine motility factor comprising *900 amino acids released by human melanoma cells.…”

Section: Lysophospholipids In Regulation Of Ah Outflow and Iopmentioning

confidence: 99%

Bioactive Lysophospholipids: Role in Regulation of Aqueous Humor Outflow and Intraocular Pressure in the Context of Pathobiology and Therapy of Glaucoma

Rao

2014

Journal of Ocular Pharmacology and Therapeutics

View full text Add to dashboard Cite

Homeostasis of aqueous humor (AH) outflow and intraocular pressure (IOP) is essential for normal vision. Impaired AH outflow through the trabecular meshwork (TM) and a resultant elevation in IOP are common changes in primary open-angle glaucoma (POAG), which is the most prevalent form of glaucoma. Although elevated IOP has been recognized as a definitive risk factor for POAG and lowering elevated IOP remains a mainstay for glaucoma treatment, little is known about the molecular mechanisms, especially external cues and intracellular pathways, involved in the regulation of AH outflow in both normal and glaucomatous eyes. In addition, despite the recognition that increased resistance to AH outflow via the conventional pathway consisting of TM and Schlemm's canal is the main cause for elevated IOP, there are no clinically approved drugs that target the conventional pathway to lower IOP in glaucoma patients. The aim of this article is to briefly review published work on the importance of bioactive lysophospholipids (eg, lysophosphatidic acid and sphingosine-1-phosphate), their receptors, metabolism, signaling, and role in the regulation of AH outflow via the TM and IOP, and to discuss pharmacological targeting of key proteins in the lysophospholipid signaling pathways to lower IOP in glaucoma patients.

show abstract

Role of sphingosine 1-phosphate and lysophosphatidic acid in fibrosis

Cited by 59 publications

References 136 publications

Metabolomic profiling in liver of adiponectin-knockout mice uncovers lysophospholipid metabolism as an important target of adiponectin action

Metabolomic profiling in liver of adiponectin-knockout mice uncovers lysophospholipid metabolism as an important target of adiponectin action

Regulation of silicosis formation by lysophosphatidic acid and its receptors

Bioactive Lysophospholipids: Role in Regulation of Aqueous Humor Outflow and Intraocular Pressure in the Context of Pathobiology and Therapy of Glaucoma

Contact Info

Product

Resources

About