Overexpression of human APOA5 in mice results in dramatically decreased plasma triglyceride levels. In this study we explored the mechanism underlying this hypotriglyceridemic effect. Initially we found that triglyceride turnover was faster in hAPOA5 transgenic mice compared to controls, and this strongly correlated with increased LPL activity in postheparin plasma. Furthermore, we show that in vitro recombinant apoAV interacts physically with lipoprotein lipase and significantly increased its activity. We show that both apoB and apoCIII are decreased in hAPOA5 transgenic mice indicating a decrease in VLDL number. To further investigate the mechanism of hAPOA5 in a hyperlipidemic background, we inter-crossed hAPOA5 and hAPOC3 transgenic mice. We found a marked decrease in VLDL triglyceride and cholesterol, as well as apolipoprotein B and CIII levels. These data indicated that apoAV induces a decrease in VLDL size by activating lipolysis and an increase of VLDL clearance. In a postprandial state, the normal triglyceride response found in wild-type mice was significantly reduced in hAPOA5 transgenics. In addition, we demonstrated that in response to this fat load in hAPOA5xhAPOC3 mice, apoAV, but not apoCIII, was redistributed from primarily HDL to VLDL. This shift of apoAV in VLDL appears to limit the increase of triglyceride by activating the lipoprotein lipase.
The joint evaluated fission and fusion nuclear data library 3.3 is described. New evaluations for neutroninduced interactions with the major actinides 235 U, 238 U and 239 Pu, on 241 Am and 23 Na, 59 Ni, Cr, Cu, Zr, Cd, Hf, W, Au, Pb and Bi are presented. It includes new fission yields, prompt fission neutron spectra and average number of neutrons per fission. In addition, new data for radioactive decay, thermal neutron scattering, gamma-ray emission, neutron activation, delayed neutrons and displacement damage are presented. JEFF-3.3 was complemented by files from the TENDL project. The libraries for photon, proton, deuteron, triton, helion and alpha-particle induced reactions are from TENDL-2017. The demands for uncertainty quantification in modeling led to many new covariance data for the evaluations. A comparison between results from model calculations using the JEFF-3.3 library and those from benchmark experiments for criticality, delayed neutron yields, shielding and decay heat, reveals that JEFF-3.3 performes very well for a wide range of nuclear technology applications, in particular nuclear energy.
Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and strongly associated with central obesity, dyslipidemia, and insulin resistance. According to the multiple-hit model of NAFLD pathogenesis, lipid accumulation drives nonalcoholic steatohepatitis (NASH) initiation by triggering oxidative stress, lipotoxicity, and subsequent activation of hepatic inflammatory responses that may progress, in predisposed individuals, to fibrosis and cirrhosis. While there is an unmet therapeutical need for NASH and fibrosis, recent preclinical studies showed that peroxisome proliferator-activated receptor (PPAR)-alpha agonism can efficiently oppose these symptoms. To dissect the relative contribution of antisteatotic versus anti-inflammatory PPAR-alpha activities in counteracting dietary-induced liver fibrosis, we used a PPAR-alpha mutant lacking its DNA-binding-dependent activity on fatty acid metabolism. Liver-specific expression of wild-type or a DNA-binding-deficient PPAR-alpha in acute and chronic models of inflammation were used to study PPAR-alpha's anti-inflammatory versus metabolic activities in NASH and fibrosis. Pharmacologically activated PPAR-alpha inhibited hepatic inflammatory responses and the transition from steatosis toward NASH and fibrosis through a direct, anti-inflammatory mechanism independent of its lipid handling properties. Conclusion: The transrepression activity of PPAR-alpha on chronic liver inflammation is sufficient to prevent progression of NASH to liver fibrosis. Dissociated PPAR-alpha agonists, selectively modulating PPAR-alpha transrepression activity, could thus be an option to prevent NASH and fibrosis progression
Objective-In this article, we studied the effect of acetyl-11-keto-␤-boswellic acid (AK␤BA), a natural inhibitor of the proinflammatory transcription factor NF-B on the development of atherosclerotic lesions in apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice. Methods and Results-Atherosclerotic lesions were induced by weekly LPS injection in apoE Ϫ/Ϫ mice. LPS alone increased atherosclerotic lesion size by Ϸ100%, and treatment with AK␤BA significantly reduced it by Ϸ50%. Moreover, the activity of NF-B was also reduced in the atherosclerotic plaques of LPS-injected apoE Ϫ/Ϫ mice treated with AK␤BA. As a consequence, AK␤BA treatment led to a significant downregulation of several NF-B-dependent genes such as MCP-1, MCP-3, IL-1␣, MIP-2, VEGF, and TF. By contrast, AK␤BA did not affect the plasma concentrations of triglycerides, total cholesterol, antioxidized LDL antibodies, and various subsets of lymphocytederived cytokines. Moreover, AK␤BA potently inhibited the IB kinase (IKK) activity immunoprecipitated from LPS-stimulated mouse macrophages and mononuclear cells leading to decreased phosphorylation of IB␣ and inhibition of p65/NF-B activation. Comparable AK␤BA-mediated inhibition was also observed in LPS-stimulated human macrophages. Conclusion-The
Objective-Both the apolipoprotein A5 and C3 genes have repeatedly been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. In mice, transgenic and knockout experiments indicate that plasma triglyceride levels are strongly altered by changes in the expression of either of these 2 genes. In humans, common polymorphisms in both genes have also been associated with plasma triglyceride concentrations. These similar findings raised the issue of the relationship between these 2 genes and altered triglycerides. Methods and Results-To address this issue, we generated independent lines of mice that either overexpressed ("double transgenic") or completely lacked ("double knockout") both apolipoprotein genes. We report that both "double transgenic" and "double knockout" mice display normal triglyceride concentrations compared with overexpression or deletion of either gene alone. Furthermore, we find that human ApoAV plasma protein levels in the "double transgenic" mice are Ϸ500-fold lower than human ApoCIII levels, supporting ApoAV as a potent triglyceride modulator despite its low concentration. Conclusions-Together, these data support that APOA5 and APOC3 independently influence plasma triglyceride concentrations but in an opposing manner. Key Words: apolipoprotein Ⅲ triglyceride Ⅲ transgenic mice A polipoproteins constitute a class of polypeptides found on plasma lipoprotein particles that play an important role in lipid transport and metabolism. Alterations in the level or structure of these molecules have been shown to dramatically impact plasma lipid concentrations and, in many cases, atherosclerosis susceptibility in humans as well as in mice. In mammals, evidence exists that some of the apolipoprotein family members are evolutionarily related as the result of gene duplication events. For instance, apolipoprotein AI, AIV, and E all share amino acid identity and similarity, supportive of a common ancestral origin. 1 We recently identified an additional member of this apolipoprotein family, named ApoAV, through the use of human-mouse genomic sequence comparisons. 2 APOA5 is located within the welldescribed APOA1/A4/C3 gene cluster on human chromosome 11q23. 3 Although APOA5 is most closely related to APOA4, manipulations of APOA5 levels in mice resulted in profound effects on plasma triglyceride concentrations, a phenotype not present in APOA4 mouse models. 2,4,5 APOA5 transgenic mice displayed significantly reduced (Ϫ70%) triglyceride concentrations whereas apoA5 knockouts had an increase (ϩ400%) in this lipid parameter. 2 Further genetic studies in humans have consistently reported strong association between common APOA5 polymorphisms and plasma triglyceride concentrations. 2,6 -11 In addition to APOA5, the neighboring APOC3 gene has also been reported to have a striking effect on human and mouse plasma triglyceride concentrations. However, APOC3 has an opposite impact on triglycerides, with transgenic mice having increased concentrations (ϩ200% to 2000%) and knocko...
a b s t r a c tThe membrane-bound Vanin-1 pantetheinase regulates tissue adaptation to stress. We investigated Vnn1 expression and its regulation in liver. Vnn1 is expressed by centrolobular hepatocytes. Using novel tools, we identify a soluble form of Vnn1 in mouse and human serum and show the contribution of a cysteine to its catalytic activity. We show that liver contributes to Vanin-1 secretion in serum and that PPARalpha is a limiting factor in serum Vnn1 production. Functional PPRE sites are identified in the Vnn1 promoter. These results indicate that serum Vnn1 might be a reliable reporter of PPARalpha activity in liver.
Growth hormone (GH) is a major metabolic regulator that functions by stimulating lipolysis, preventing protein catabolism, and decreasing insulin-dependent glucose disposal. Modulation of hepatic sensitivity to GH and the downstream effects on the GH/IGF1 axis are important events in the regulation of metabolism in response to variations in food availability. For example, during periods of reduced nutrient availability, the liver becomes resistant to GH actions. However, the mechanisms controlling hepatic GH resistance are currently unknown. Here, we investigated the role of 2 tetraspanning membrane proteins, leptin receptor overlapping transcript (LEPROT; also known as OB-RGRP) and LEPROT-like 1 (LEPROTL1), in controlling GH sensitivity. Transgenic mice expressing either human LEPROT or human LEPROTL1 displayed growth retardation, reduced plasma IGF1 levels, and impaired hepatic sensitivity to GH, as measured by STAT5 phosphorylation and Socs2 mRNA expression. These phenotypes were accentuated in transgenic mice expressing both proteins. Moreover, gene silencing of either endogenous Leprot or Leprotl1 in H4IIE hepatocytes increased GH signaling and enhanced cell-surface GH receptor. Importantly, we found that both LEPROT and LEPROTL1 expression were regulated in the mouse liver by physiologic and pathologic changes in glucose homeostasis. Together, these data provide evidence that LEPROT and LEPROTL1 influence liver GH signaling and that regulation of the genes encoding these proteins may constitute a molecular link between nutritional signals and GH actions on body growth and metabolism.
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