Endotoxic Shock and the Sphingomyelin Pathway
Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison in Endotoxin in Health and Disease, 2020
A comparison of the structures of lipid A and cer-amide is shown in Figure 1. Carbons 1–3 of the reducing glucosamine of lipid A closely resemble Carbons 1–3 of ceramide (Fig. 1, boxed). This region is conserved in all biologically active LPS and ceramide analogs, and nearly all other portions of the molecules can be deleted or altered without destroying bioactivity. Experiments using molecular modeling and conformational dynamics to generate energy minimized structures of the reducing glucosamine of lipid A (GlcN-1, dephosphorylated form) and ceramide showed that positions C-l, C-2, and C-3 and their functional groups were nearly superimposible. A similar result was obtained when the 1-phosphylated forms of each lipid were compared. In contrast, molecular modeling of 1,2-diacylglycerol generated showed far less similarity.
Fetal and Neonatal Development of the Exocrine Pancreas
Jean Morisset, Travis E. Solomon in Growth of the Gastrointestinal Tract: Gastrointestinal Hormones and Growth Factors, 2017
Secretagogues such as CCK and carbachol act by first binding to specific receptors on the surface of the acinar cells. After binding, a series of events collectively termed “stimulus-secretion coupling” take place which finally result in secretion of enzymes from the acinar cells by exocytosis. Pancreatic exocrine secretion is stimulated by secretagogues that act primarily through either the adenylate cyclase system (secretin and vasoactive intestinal polypeptide) or the phosphatidylinositol pathway (CCK and cholinergic agents). The binding of cholecystoki-nin and cholinergic agents to their respective receptors results in the release of inositol trisphosphate and 1,2-diacylglycerol. Inositol trisphosphate induces calcium mobilization and activates calmodulin-dependent protein kinases. At the same time, 1,2-diacyglycerol activates and translocates protein kinase C from a cytosolic to a membraneous site. Taken together, protein kinase C activation, calcium mobilization and subsequent activation of calmodulin dependent protein kinase are viewed as important intermediary steps leading to secretion by the exocrine pancreas.32
Lower-intensity aerobic endurance sports
Nick Draper, Helen Marshall in Exercise Physiology, 2014
The process of lipolysis takes place within the adipocyte cytosol and involves a series of three reactions. Through the hydrolysis of a triglyceride (i.e. lipolysis), water added to the reactants enables one of the fatty acid (acyl) molecules to be removed from the glycerol backbone in each of the three reactions. These reactions are illustrated in Figure 12.5. In the first reaction, a fatty acid is removed from the third carbon molecule of glycerol leaving 1,2-diacylglycerol with fatty acids still attached to carbons 1 and 2. The second reaction removes the fatty acid from the first glycerol carbon leaving 2-monoacylglycerol. These first two reactions are catalysed by the enzyme, hormone-sensitive lipase (HSL). In the final reaction, the remaining fatty acid is cleaved from the glycerol molecule, catalysed by monoglyceride lipase along with HSL.
Managing chronic kidney disease in diabetes patients with the latest chemical therapies
Published in Expert Review of Clinical Pharmacology, 2019
Activation of PKC pathway is identified as a crucial mechanism in the development and progression of CKD in diabetic patients [42]. PKC enzymes are usually activated by the increased concentration of diacylglycerol or calcium ions. Persistent hyperglycemia may result in the overproduction of diacylglycerol, which activates PKC isoforms in different tissues [42]. Abnormalities of PKC pathway may affect blood flow and regulation, leukocyte adhesion, regulation of endothelial permeability, extracellular matrix synthesis/turnover, cytokine, and growth factor activation, all of which are associated with the pathogenesis of CKD in diabetic patients [42]. It was found that the PKC-α and PKC-β isoforms are bound up with CKD. Hence, inhibition of PKC is considered as a novel approach for the management of CKD.
The effect of adenosine monophosphate-activated protein kinase on lipolysis in adipose tissue: an historical and comprehensive review
Published in Archives of Physiology and Biochemistry, 2022
Daniel Boone-Villa, Janeth Ventura-Sobrevilla, Asdrúbal Aguilera-Méndez, Joel Jiménez-Villarreal
In the first stage, one fatty acid chain is removed from the TG by the action of a TG lipase producing diacylglycerol (DG). Until recently, it was believed that the hormone sensitive lipase (HSL) controlled this step. Posterior studies reported that this enzymatic activity is independent of HSL action, and this discovery triggered the characterisation of novel TG lipases (Osuga et al.2000, Wang et al.2001, Haemmerle et al.2002), the most important of these novel enzymes is the adipose triglyceride lipase (ATGL) (Villena et al.2004), that also presents DG lipase activity but to a minor extent. In the second step of the lipolytic process, the DG is broken down to form monoacylglyceride, principally by the action of HSL. This enzyme has a reported affinity for DG eleven times greater than for TG (Holm 2003). In the final step of the lipolytic process, Monoglyceride Lipase releases the last fatty acid chain from the glycerol skeleton of the monoacylglyceride (Fredrikson et al. 1986). The net result of the complete process is a total of three NEFA molecules and one glycerol molecule released from one completely hydrolysed TG (Large et al.2004). The control of the lipolytic process is more complex than this 3-steps scheme: other participants like Perilipins-family proteins (Sztalryd and Brasaemle 2017), kinases like the protein kinase A (PKA) and AMPK (Londos et al.1999, Macpherson et al.2016), hormones like adrenalin, catecholamines, and leptin (Chaves et al. 2011, Zechner et al. 2017), genetic controllers like CGI-58 and G0S2 (MacPherson et al.2013, Brown and Mark Brown 2017, Zhang et al.2017) and even substrate-related signals (Nagy et al.2014) participate in its regulation.
Peroxisome proliferator-activated receptor agonists and antagonists: a patent review (2014-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Ichiro Takada, Makoto Makishima
Janssen Pharmaceutica NV has claimed the combination of any PPAR agonist and DGAT inhibitor in the treatment of metabolic disease, such as hypertriglyceridemia [61]. DGAT catalyzes the synthesis of triacylglycerol (triglyceride) from diacylglycerol. Mice deficient in the Dgat1 gene are resistant to diet-induced obesity and show lower triglyceride levels and decreased resistance to insulin and leptin [62]. The inventors reported that DGAT inhibitor treatment increases GLP-1 levels and that the combination of DGAT inhibitor and PPARα agonist induces weight loss more effectively than treatment with each compound alone [61].
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