Autotaxin (ATX) is a secreted nucleotide pyrophosphatase/phosphodiesterase that functions as lysophospholipase D to produce the lipid mediator lysophosphatidic acid (LPA), mitogen, chemoattractant, and survival factor for many cell types. The ATX-LPA signaling axis has been implicated in angiogenesis, chronic inflammation, fibrotic diseases tumor progression, making this system an attractive target therapy. However, potent selective nonlipid inhibitors of ATX are currently not available. By...

Abstract Fatty acid synthase (FASN) and ATP-citrate lyase, key enzymes of de novo lipogenesis, are significantly upregulated activated in many cancers portend poor prognosis. Even though the role lipogenesis providing proliferative survival advantages to cancer cells has been described, impact aberrant activation lipogenic on progression remains unknown. In this study, we found that elevated expression FASN is associated with advanced stages colorectal (CRC) liver metastasis, suggesting it...

Plasma sphingosine-1-phosphate (S1P) regulates vascular permeability, and plasma lymph S1P guide lymphocyte egress from lymphoid organs. is made intracellularly, little known about how delivered into circulatory fluids. Here, we find that mice without the major facilitator superfamily transporter Spns2 have a profound reduction in S1P, but only minor decrease S1P. Spns2-deficient redistribution of lymphocytes spleen to nodes loss circulating lymphocytes, consistent with normal directed by...

Abstract A chemoenzymatic platform for the synthesis of S ‐adenosyl‐ L ‐methionine (SAM) analogues compatible with downstream SAM‐utilizing enzymes is reported. Forty‐four non‐native S/Se‐alkylated Met were synthesized and applied to probing substrate specificity five diverse methionine adenosyltransferases (MATs). Human MAT II was among most permissive MATs analyzed enabled 29 SAM analogues. As a proof concept feasibility natural product “alkylrandomization”, small set...

Background: Previous studies demonstrated that coplanar polychlorinated biphenyls (PCBs) promote proinflammatory gene expression in adipocytes. PCBs are highly lipophilic and accumulate adipose tissue, a site of insulin resistance persons with type 2 diabetes.Objectives: We investigated the vitro vivo effects on tumor necrosis factor α (TNF-α) glucose homeostasis lean obese mice.Methods: quantified tolerance, as well TNF-α levels, liver, muscle, tissue male C57BL/6 mice administered vehicle,...

Recent studies suggest that sphingolipid metabolism is altered during type 2 diabetes. Increased levels of the ceramide are associated with insulin resistance. However, a role for sphingolipids in pancreatic beta cell function, or production, and release remains to be established. Our MIN6 cells mouse islets demonstrate glucose stimulates an intracellular rise sphingolipid, sphingosine 1-phosphate (S1P), whereas sphingomyelin remain unchanged. The increase S1P by due activation kinase...

Ceramide-1-phosphate (C1P) is a bioactive lipid that, in contrast to ceramide, an antiapoptotic molecule released from cells that are damaged and "leaky." As reported recently, C1P promotes migration of hematopoietic cells. In this article, we tested the hypothesis upon tissue damage may play underappreciated role chemoattraction various types stem endothelial involved tissue/organ regeneration. We show for first time upregulated tissues chemoattracts bone marrow (BM)-derived multipotent...

Abstract Autotaxin (ATX) generates the lipid mediator lysophosphatidic acid (LPA). ATX-LPA signalling is involved in multiple biological and pathophysiological processes, including vasculogenesis, fibrosis, cholestatic pruritus tumour progression. ATX has a tripartite active site, combining hydrophilic groove, hydrophobic lipid-binding pocket tunnel of unclear function. We present crystal structures rat bound to 7α-hydroxycholesterol bile salt tauroursodeoxycholate (TUDCA), showing how...

Bisphenol A (BPA) is a base chemical used extensively in many consumer products. BPA has recently been associated with increased risk of cardiovascular disease (CVD) multiple large-scale human population studies, but the underlying mechanisms remain elusive. We previously reported that activates pregnane X receptor (PXR), which acts as xenobiotic sensor to regulate metabolism and pro-atherogenic effects animal models upon activation. Interestingly, potent agonist PXR does not activate mouse...

Lysophosphatidic acid (LPA) is a bioactive lipid mediator. Concentrations of the major LPA species in mouse plasma decreased uniformly following administration potent selective inhibitor LPA-generating lysophospholipase D autotaxin, identifying an active mechanism for removal from circulation. LPA, akylglycerol phosphate (AGP), sphingosine 1-phosphate (S1P), and variety structural mimetics these lipids, including phosphatase-resistant phosphonate analogs were rapidly eliminated (t1/2 < 30 s)...

Lipid phosphate phosphatase 3 (LPP3), encoded by the PPAP2B gene, is an integral membrane enzyme that dephosphorylates, and thereby terminates, G-protein-coupled receptor-mediated signaling actions of lysophosphatidic acid (LPA) sphingosine-1-phosphate. LPP3 essential for normal vascular development in mice, a common polymorphism associated with increased risk coronary artery disease humans. Herein, we investigate function endothelial to understand its role human disease.We developed mouse...

Coplanar polychlorinated biphenyls (PCBs) promote adipocyte inflammation and impair glucose homeostasis in lean mice. The diabetes-promoting effects of lipophilic PCBs have been observed only during weight loss obese molecular mechanisms linking PCB exposures to impaired metabolism are unclear.In this study we tested the hypothesis that coplanar act at aryl hydrocarbon receptors (AhRs) adipose mice loss.PCB-77 administration insulin tolerance LF (low fat diet)-fed control (AhR(fl/fl)) but...

Lipins are phosphatidic acid phosphatases with a pivotal role in regulation of triglyceride and glycerophospholipid metabolism. Lipin1 is also an amplifier PGC-1α, nuclear coactivator PPAR-α responsive gene transcription. do not contain recognized membrane-association domains, but interaction these enzymes cellular membranes necessary for access to their phospholipid substrate. We identified conserved polybasic amino motif N-terminal domain previously implicated as determinant localization...

Brown adipose tissue is a thermogenic organ that dissipates stored energy as heat to maintain body temperature. This process may also provide protection from development of diet-induced obesity. We report the bioactive lipid mediator lysophosphatidic acid (LPA) markedly decreases differentiation cultured primary brown adipocyte precursors, whereas potent selective inhibitors LPA-generating enzyme autotaxin (ATX) promote differentiation. Transgenic mice overexpressing ATX exhibit reduced...

Appalachian active coal fire sites were selected for the isolation of bacterial strains belonging to class actinobacteria. A comparison high-resolution electrospray ionization mass spectrometry (HRESIMS) and ultraviolet (UV) absorption profiles from isolate extracts natural product databases suggested Streptomyces sp. RM-4-15 produce unique metabolites. Four new pyranonaphthoquinones, frenolicins C–F (1–4), along with three known analogues, frenolicin (6), B (7), UCF76-A (8), isolated...

The ORM1 (Saccharomyces cerevisiae)-like proteins (ORMDLs) and their yeast orthologs, the Orms, are negative homeostatic regulators of initiating enzyme in sphingolipid biosynthesis, serine palmitoyltransferase (SPT). Genome-wide association studies have established a strong correlation between elevated expression endoplasmic reticulum protein ORMDL3 risk for childhood asthma. Here we test notion that levels decrease biosynthesis. This was tested cultured human bronchial epithelial cells...

PIPKIγ90 binds talin and localizes at focal adhesions (FAs). PIP2 generated by is essential for FA formation cell migration. On the other hand, β integrin tail compete overlapping binding sites on talin. Enhanced PIPKIγ90-talin interaction suppresses to integrin. It unknown how removed from complex after on-site production during Here we show that a substrate HECTD1, an E3 ubiquitin ligase regulating HECTD1 ubiquitinated Lys97 resulted in degradation. Expression of PIPKIγ90K97R enhanced PIP3...

Abstract A chemoenzymatic platform for the synthesis of S ‐adenosyl‐ L ‐methionine (SAM) analogues compatible with downstream SAM‐utilizing enzymes is reported. Forty‐four non‐native S/Se‐alkylated Met were synthesized and applied to probing substrate specificity five diverse methionine adenosyltransferases (MATs). Human MAT II was among most permissive MATs analyzed enabled 29 SAM analogues. As a proof concept feasibility natural product “alkylrandomization”, small set...