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Rare forms of interstitial lung disease
Published in Muhunthan Thillai, David R Moller, Keith C Meyer, Clinical Handbook of Interstitial Lung Disease, 2017
Niemann–Pick disease is a group of disorders characterized by accumulation of sphingomyelin, and it is inherited in an autosomal recessive pattern. These disorders are caused by mutations in the sphingomyelin phosphodiesterase-1 gene or genes that control cellular processing and transport of low-density cholesterol. Intracellular accumulation of sphingomyelin or unesterified cholesterol leads to disease manifestations that commonly include organomegaly and neurologic deficits with variable age of onset. ILD due to parenchymal accumulation of lipid-laden macrophages, alveolar proteinosis, recurrent respiratory infections and respiratory failure can occur in these patients (139,150–153). At present, there is no cure or enzyme replacement therapy for Niemann–Pick disease.
What can we learn from the platelet lipidome?
Published in Platelets, 2023
Gaëtan Chicanne, Jean Darcourt, Justine Bertrand-Michel, Cédric Garcia, Agnès Ribes, Bernard Payrastre
The combination of technologies can improve the identification and quantification of lipids. For instance, a recent study integrating shotgun analysis and targeted lipidomics performed on human and mouse platelets has provided a first quantitative analysis of mouse platelet lipidome [18,19]. This study identified about 400 lipid species, 15 being the most abundant ones and less than 20% had an alteration of their abundance following thrombin stimulation. Interestingly, using a mouse model of sphingomyelin phosphodiesterase deficiency, the authors observed a correlation between an increase in lysosphingomyelin concentration and platelet response inhibition. Although the mechanisms involved remain unclear this study sheds light on a novel mechanism regulating platelet function. In platelets, the sphingolipids metabolism is highly active. For instance, sphingosine-1-phosphate, generated by sphingosine kinase, is released by activated platelets and acts as an extracellular mediator stimulating specific G-protein coupled receptors [20].
Lipidomics reveal aryl hydrocarbon receptor (Ahr)-regulated lipid metabolic pathway in alpha-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis
Published in Xenobiotica, 2019
Bao-Long Wang, Chang-Wen Zhang, Liang Wang, Kun-Long Tang, Naoki Tanaka, Frank J. Gonzalez, Yong Xu, Zhong-Ze Fang
The alteration of lipid profile induced by ANIT treatment was investigated in the present study, and many lipid components changed, including PC 16:0, 20:4, PC 16:0, 22:6, PC 16:0, 18:2, LPC 18:2, PC 18:2, LPC 18:1, PC 18:1, 14:0, SM 18:1, 16:0, oleoylcarnitine and palmitoylcarnitine. Furthermore, the relevant molecular mechanisms resulting in the alteration of these lipid components were investigated. Choline kinase (Chk) a, a key enzyme catalyzing the first reaction in the choline pathway for biosynthesis of PC (Bansal et al., 2012), was detected to increase in ANIT-induced liver injury, which can explain why the level of many PC components increased in ANIT-treated mice. The elevated level of PC furtherly resulted in the increase of LPC, SM and fatty acid–carnitine conjugate through the biotransformation of PC components towards these components. The alteration of lipid components was furtherly complicated by the altered expression of Smpd3 and Scd1. Sphingomyelin phosphodiesterase (SMPD), a hydrolase enzyme converting SM to PC components (Hannun, 1994), can furtherly increase the levels of PC through biotransformation of SM to PC. Stearoyl-CoA desaturase 1 (SCD1), an endoplasmic reticulum (ER) enzyme is responsible for biosynthesis of oleic acid (18:1) and palmitoleic acid (16:1) from stearic acid (18:0) and palmitic acid (16:0), respectively. The inhibition of SCD1 has been reported to increase the level of saturated LPC and decrease the level of unsaturated LPC (Chen et al., 2008). Therefore, the alteration of lipid components in ANIT-treated mice will be the final results affected by the combined change of all these genes.
The ceramide-S1P pathway as a druggable target to alleviate peripheral neuropathic pain
Published in Expert Opinion on Therapeutic Targets, 2020
Michiel Langeslag, Michaela Kress
Ceramide and other sphingolipid metabolites derived from ceramide, like sphingosine-1-phosphate (S1P) and lactosylceramide (LacCer) have important pathophysiological functions, mainly in inflammatory-related diseases and inflammatory responses [7]. Secretion of pro-inflammatory cytokines by immune cells activate the conversion of sphingomyelin into ceramide by sphingomyelin phosphodiesterase isoenzymes (SMPDs). Ceramide can be converted to glucosylceramide (glucosylceramide synthase) which acts as a substrate for lactosylceramide synthase (LCS) to produce LacCer Figure 1. On the one hand, S1P can be generated from ceramide through conversion to sphingosine by ceramidases and subsequent phosphorylation by sphingosine kinases (SPHK1, SPHK2), which forms the rate limiting step in S1P production. S1P has potential intracellular actions [8,9]. Normally, intracellular S1P levels are remained low by either dephosphorylation of S1P by sphingosine phosphatase or irreversible degradation by S1P lyases [10]. S1P with its polar headgroup connected to hydrophobic acyl chain can act as diffusible, intercellular signaling molecule through secretion from cells. The most widely studied S1P transporter is SPNS2, S1P-mediated transport is increased after overexpression of SNPS2. Reversely, down-regulation of SPNS2 decreases S1P release [11–13]. In addition to S1P, SPNS2 can also transport S1P analogs like FTY720-P [11,13]. Also, other transporters for S1P exist such as ABCA1 [14], ABCC1 [15–18], ABCG2 [17] and the recently discovered Mfsd2b [19,20]. Mfsd2b has been identified in erythrocytes and platelets and belongs to the family of transporters as SPNS2.