Written informed consent was obtained from all patients and volunteers

Written informed consent was obtained from all patients and volunteers

inflammation and fibrosis . Recent evidence suggests that NAFLD is responsible for the development of hepatocellular carcinoma , and the population of NAFLD-associated HCC patients is clearly growing. In addition to such diseases associated with metabolic syndrome, many studies in humans and mice have shown a strong correlation between obesity and autoimmune diseases, which are accompanied by increased levels of autoantibodies. In addition, it is known that obesity decreases multiple types of immune function including natural killer cell cytotoxicity, maturation of macrophages, and polymorphonuclear bactericidal capacity, resulting in increase in susceptibility to bacterial and viral infection. Therefore, the development of therapeutic strategies to regulate obesity is strongly desired. Recently, we found that apoptosis inhibitor of macrophage, a circulating protein initially identified as a supporter of macrophage survival, plays a preventive role in obesity progression. AIM is produced solely by tissue macrophages under transcriptional regulation by nuclear JW-55 biological activity receptor liver X receptor/retinoid X receptor heterodimers. As a secreted molecule, AIM is detected in human and mouse blood at varying levels; and circulating AIM increases with the progression of obesity in mice fed a high fat diet . Circulating AIM is incorporated into adipocytes via CD36-mediated endocytosis, where it directly binds and inactivates cytoplasmic fatty acid synthase . This response reduces the production of lipid droplet-coating proteins, such as fat-specific protein 27 and perilipin, thereby decreasing triacylglycerol deposition within adipocytes. Accordingly, adipocyte hypertrophy was more advanced and the mass of visceral adipose tissues was greater in 1 A Novel Strategy to Increase Circulating AIM AIM2/2 PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19656604 mice than in AIM+/+ mice fed an HFD. This HFDinduced hyperobese phenotype was abolished by administering recombinant AIM to the AIM2/2 mice. These findings suggest that AIM might be an effective therapeutic tool to regulate obesity progression. Interestingly, AIM associates with the immunoglobulin M pentamer in blood, an association which protects AIM from renal excretion and thus maintains relatively high circulating concentrations . Consistently, a strong correlation between AIM and natural IgM levels in the blood has been found in both humans and mice, clearly indicating that levels of circulating AIM are dependent on natural IgM levels, except in cases in which AIM expression is abrogated in macrophages. Accordingly, administration of AIM into mice lacking circulating IgM, such as recombinase-activating gene 1-deficient mice or secreted-type IgM-deficient mice, was not effective for sustained increases in AIM levels, as the free AIM was rapidly excreted in the urine. Similarly, increases in blood AIM levels in wild-type animals, which have normal levels of IgM, may not be achieved by AIM administration, as most circulating IgM is already associated with endogenous AIM. In this study, we evaluated new strategies for increasing circulating AIM levels in the presence or absence of IgM. We synthesized an IgM-Fc protein as well as a binding complex of Fc and AIM and evaluated their ability to augment circulating AIM levels without any undesired immune activation. In view of the potential for future use in humans, we used human IgM-Fc and human AIM for this study in a mouse model. lized at pH 4.0 to 2800 resonance units in one flow cell on a CM5 sensor chip, whe

Proton-pump inhibitor

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