Aspirin reduces hypertriglyceridemia by lowering VLDL-triglyceride production in mice fed a high-fat diet

Diabetes mellitus: pathophysiological changes and therap

NF-kB activation and polyubiquitin conjugation are required for pulmonary inflammation-induced diaphragm atrophy.

Loss of diaphragm muscle strength in inflammatory lung disease contributes to mortality and is associated with diaphragm fiber atrophy. Ubiquitin (Ub) 26S-proteasome system (UPS) dependent protein breakdown, which mediates muscle atrophy in a number of physiological and pathological conditions, is elevated in diaphragm muscle of patients with chronic obstructive pulmonary disease. Nuclear Factor kappa B (NF-kappaB), an essential regulator of many inflammatory processes, has been implicated in the regulation of poly-Ub conjugation of muscle proteins targeted for proteolysis by the UPS. Here we test if NF-kappaB activation in diaphragm muscle and subsequent protein degradation by the UPS are required for pulmonary inflammation-induced diaphragm atrophy. Acute pulmonary inflammation was induced in mice by intra-tracheal lipopolysaccharide instillation. Fiber cross sectional area, ex vivo tyrosine release, protein poly-Ub conjugation and inflammatory signalling were determined in diaphragm muscle. The contribution of NF-kappaB or the UPS to diaphragm atrophy was assessed in mice with intact or genetically repressed NF-kappaB signalling or attenuated poly-Ub conjugation, respectively. Acute pulmonary inflammation resulted in diaphragm atrophy measured by reduced muscle fiber cross sectional area. This was accompanied by diaphragm NF-kappaB activation, and proteolysis, measured by tyrosine release from the diaphragm. Poly-Ub conjugation was increased in diaphragm; as was the expression of muscle specific E3 Ub-ligases. Genetic suppression of poly-Ub conjugation prevented inflammation-induced diaphragm muscle atrophy as did muscle specific inhibition of NF-kappaB signalling. In conclusion, the present study is the first to demonstrate that diaphragm muscle atrophy resulting from acute pulmonary inflammation requires NF-kappaB activation and UPS-mediated protein degradation

Hepatocyte-specific Inflammation Directly Enhances VLDL-triglyceride Production in Mice

Diabetes mellitus: pathophysiological changes and therap

NF-kappa B Activation Is Required for the Transition of Pulmonary Inflammation to Muscle Atrophy

Rationale Disease exacerbations and muscle wasting are negative prognostic factors of COPD. Transient systemic inflammation and malnutrition have been implicated in skeletal muscle wasting following acute exacerbations of COPD. However, the interaction between systemic inflammation and malnutrition in their contribution to muscle atrophy, as well as the molecular basis underlying the transition of systemic inflammation to muscle atrophy remain unresolved.Methods Pulmonary inflammation was induced in mice by intra-tracheal (IT) lipopolysaccharide (LPS) instillation to model acute disease exacerbation. Systemic inflammation, nutritional intake, body and muscle weights were determined. Muscle inflammatory and atrophy signalling were examined, and the effect of muscle specific inactivation of Nuclear Factor kappa B (NF-kB) on muscle atrophy was assessed in genetically modified mice. Results IT-LPS instillation was followed by markedly elevated circulating cytokine levels and NF-kB activation in extra-pulmonary tissues, including skeletal muscle. IT-LPS administration increased the expression of muscle E3 Ub-ligases which govern muscle proteolysis, in particular MuRF1, and caused rapid loss of muscle mass. Reduced food intake only partially accounted for the observed muscle atrophy and did not activate NF-kB in muscle. Rather, plasma transfer experiments revealed the presence of NF-kB- and atrophy-signalling properties in the circulation of IT-LPS treated mice. Genetic inhibition of muscle NF-kB activity suppressed IT-LPS-induced MuRF1 expression and resulted in significant sparing of muscle tissue. Conclusion Systemic inflammation and malnutrition contribute to muscle wasting induced by acute pulmonary inflammation via distinct mechanisms, and muscle NF-kB activation is required for the transition from inflammatory to muscle atrophy signalling

Tag polymorphisms at the A20 (TNFAIP3) locus are associated with lower gene expression and increased risk of coronary artery disease in type 2 diabetes

A20 or tumor necrosis factor (TNF)-induced protein 3 (TNFAIP3) is a negative regulator of nuclear factor-kappa B (NF-kappa B). We have investigated whether polymorphisms in this gene are associated with increased atherosclerosis in diabetic patients. Five tag single nucleotide polymorphisms (SNPs) were typed in 479 type 2 diabetic patients from Boston, including 239 coronary artery disease (CAD)positive case subjects and 240 CAD-negative control subjects. Two tag SNPs (rs5029930 and rs610604) were independently associated with CAD; adjusted odds ratios (ORs) for minor allele carriers were 2.3 (95% CI 1.4-3.8, P = 0.001) and 2.0 (1.3-2.9, P = 0.0008), respectively. The association with rs610604 was dependent on glycemic control, with ORs of 3.9 among subjects with A1C 7.0% (P for interaction = 0.015). A similar interaction pattern was found among 231 CAD-positive and 332 CAD-negative type 2 diabetic patients from Italy (OR 2.2, P = 0.05 vs. OR 0.9, P = 0.63 in the low vs. high A1C strata, P for interaction = 0.05). Quantitative RT-PCR in blood mononuclear cells from 83 nondiabetic subjects showed that rs610604 and rs5029930 minor allele homozygotes have 30-45% lower levels of A20 mRNA than major allele homozygotes, and heterozygotes have intermediate levels (P = 0.04 and 0.028, respectively). These findings point to variability in the A20/TNFAIP3 gene as a modulator of CAD risk in type 2 diabetes. This effect is mediated by allelic differences in A20 expression

DELETE LIVER-SPECIFIC IKK-beta ACTIVATION SEVERELY AGGRAVATES ATHEROSCLEROSIS DEVELOPMENT IN APOE*3-LEIDEN MICE

Pathogenesis and treatment of chronic pulmonary disease

Hepatocyte-specific IKKbeta expression aggravates atherosclerosis development in APOE*3-Leiden mice

Item does not contain fulltextOBJECTIVE: The liver is the key organ involved in systemic inflammation, but the relation between hepatic inflammation and atherogenesis is poorly understood. Since nuclear factor-kappaB (NF-kappaB) is a central regulator of inflammatory processes, we hypothesized that chronically enhanced hepatic NF-kappaB activation, through hepatocyte-specific expression of IkappaB kinase-beta (IKKbeta) (LIKK), will aggravate atherosclerosis development in APOE*3-Leiden (E3L) mice. METHODS AND RESULTS: E3L.LIKK and E3L control littermates were fed a Western-type diet for 24 weeks. E3L.LIKK mice showed a 2.3-fold increased atherosclerotic lesion area and more advanced atherosclerosis in the aortic root with less segments without atherosclerotic lesions (11% vs. 42%), and more segments with mild (63% vs. 44%) and severe (26% vs. 14%) lesions. Expression of LIKK did not affect basal levels of inflammatory parameters, but plasma cytokine levels tended to be higher in E3L.LIKK mice after lipopolysaccharide (LPS) administration. E3L.LIKK mice showed transiently increased plasma cholesterol levels, confined to (V)LDL. This transient character resulted in a mild (+17%) increased cumulative plasma cholesterol exposure. CONCLUSION: We conclude that selective activation of NF-kappaB in hepatocytes considerably promotes atherosclerosis development which is (at least partly) explained by an increased sensitivity to proinflammatory triggers and transiently increased plasma cholesterol levels