Platelets are relatively short-lived, anucleated cells that are essential for proper hemostasis. The regulation of platelet survival in the circulation remains poorly understood. The process of platelet activation and senescence in vivo is associated with processes similar to those observed during apoptosis in nucleated cells, including loss of mitochondrial membrane potential, caspase activation, phosphatidylserine (PS) externalization, and cell shrinkage. ABT-737, a potent antagonist of Bcl-2, Bcl-X L , and Bcl-w, induces apoptosis in nucleated cells dependent on these proteins for survival. In vivo, ABT-737 induces a reduction of circulating platelets that is maintained during drug therapy, followed by recovery to normal levels within several days after treatment cessation. Whole body scintography utilizing [111] Indium-labeled platelets in dogs shows that ABT-737-induced platelet clearance is primarily mediated by the liver. In vitro, ABT-737 treatment leads to activation of key apoptotic processes including cytochrome c release, caspase-3 activation, and PS externalization in isolated platelets. Despite these changes, ABT-737 is ineffective in promoting platelet activation as measured by granule release markers and platelet aggregation. Taken together, these data suggest that ABT-737 induces an apoptosis-like response in platelets that is distinct from platelet activation and results in enhanced clearance in vivo by the reticuloendothelial system.

Mammalian carboxylesterases hydrolyze a wide range of xenobiotic and endogenous compounds, including lipid esters. Physiological functions of carboxylesterases in lipid metabolism and energy homeostasis in vivo have been demonstrated by genetic manipulations and chemical inhibition in mice, and in vitro through (over)expression, knockdown of expression, and chemical inhibition in a variety of cells. Recent research advances have revealed the relevance of carboxylesterases to metabolic diseases such as obesity and fatty liver disease, suggesting these enzymes might be potential targets for treatment of metabolic disorders. In order to translate pre-clinical studies in cellular and mouse models to humans, differences and similarities of carboxylesterases between mice and human need to be elucidated. This review presents and discusses the research progress in structure and function of mouse and human carboxylesterases, and the role of these enzymes in lipid metabolism and metabolic disorders.

Excessive accumulation of triacylglycerol in peripheral tissues is tightly associated with obesity and has been identified as an independent risk factor for insulin resistance, type 2 diabetes, and cardiovascular complications. Here we show that ablation of carboxylesterase 3 (Ces3)/triacylglycerol hydrolase (TGH) expression in mice (Tgh(-/-)) results in decreased plasma triacylglycerol, apolipoprotein B, and fatty acid levels in both fasted and fed states. Despite the attenuation of very low-density lipoprotein secretion, TGH deficiency does not increase hepatic triacylglycerol levels. Tgh(-/-) mice exhibit increased food intake, respiratory quotient, and energy expenditure without change in body weight. These metabolic changes are accompanied by improved insulin sensitivity and glucose tolerance. Tgh(-/-) mice have smaller sized pancreatic islets but maintain normal glucose-stimulated insulin secretion. These studies demonstrate the potential of TGH as a therapeutic target for lowering blood lipid levels.

In this paper we present an experimental evaluation of adaptive and non-adaptive visual servoing in 3,6

Increased lipogenesis, together with hyperlipidemia and increased fat deposition, contribute to obesity and associated metabolic disorders including nonalcoholic fatty liver disease. Here we show that carboxylesterase 1/esterase-x (Ces1/Es-x) plays a regulatory role in hepatic fat metabolism in the mouse. We demonstrate that Ces1/Es-x knockout mice present with increased hepatic lipogenesis and with oversecretion of apolipoprotein B (apoB)-containing lipoproteins (hepatic very-low density lipoproteins), which leads to hyperlipidemia and increased fat deposition in peripheral tissues. Consequently, Ces1/Es-x knockout mice develop obesity, fatty liver, hyperinsulinemia, and insulin insensitivity on chow diet without change in food intake and present with decreased energy expenditure. Ces1/Es-x deficiency prevents the release of polyunsaturated fatty acids from triacylglycerol stores, leading to an upregulation of sterol regulatory element binding protein 1c-mediated lipogenesis, which can be reversed with dietary x-3 fatty acids. Conclusion: These studies support a role for Ces1/Es-x in the partitioning of regulatory fatty acids and concomitant control of hepatic lipid biosynthesis, secretion, and deposition. (HEPATOLOGY 2012;56:2188-2198 T he liver is the central metabolic organ that regulates key pathways in lipid metabolism including fatty acid (FA) b-oxidation, lipogenesis, as well as lipoprotein uptake and secretion in response to nutritional and hormonal signals. 1 Dysregulation of hepatic lipid metabolic pathways results in the development of hepatic steatosis, which in turn contributes to the development of chronic hepatic inflammation, insulin resistance, and liver damage. 2,3 We have previously demonstrated that carboxylesterase 3/triacylglycerol hydrolase (Ces3/TGH) (recently annotated Ces1d) 4 plays an important role in the provision of lipid substrates for the assembly of apolipoprotein B (apoB)-containing lipoproteins. 5 Ablation of Ces3/Tgh/ Ces1d expression in mice leads to decreased plasma lipids, including triacylglycerol (TG) and nonesterified fatty acids (NEFA), along with decreased apoB100 secretion. 6 Mouse Ces1/Es-x (recently annotated Ces1g) 4 shares $76% protein sequence identity with mouse Ces3/ TGH/Ces1d, including conserved lipase/esterase catalytic triad amino acid residues and regions of the lid domain. 7,8 Hepatic Ces1/Es-x expression was found to be augmented in mice fed either a ketogenic 9 or a cholate supplemented 8 diet and is reduced in stearoylCoA desaturase-1 (SCD-1)-deficient mice fed a verylow-fat diet. 10 It has also been reported that ectopic expression of Ces1/Es-x in McArdle-RH7777 attenuates