With improvements in the understanding of the mechanism of duodenogastric mucosal acid Selleckchem Ku-0059436 sensing, coupled with improvements of the methodology for luminal pH monitoring, novel therapies will be developed for FD. Until then, it remains a vexing and frustrating therapeutic challenge for clinicians. We thank Miss Coleen Palileo (University of California, Los Angeles) for her assistance with the manuscript preparation. This Editorial is supported by the Veterans Affairs Merit Review Award and NIH-NIDDK R01 DK54221 (JDK). “
“Obesity is a calorie-excessive state associated
with high risk of diabetes, atherosclerosis, and certain types of tumors. Obesity may induce inflammation and insulin resistance (IR). We found that the expression of interferon (IFN) regulatory factor 9 (IRF9), a major transcription factor mediating IFN responses, was lower in livers of obese mice than in those of their lean counterparts.
Furthermore, whole-body IRF9 knockout (KO) mice were more obese and had aggravated IR, hepatic steatosis, and inflammation after chronic high-fat diet feeding. In contrast, adenoviral-mediated hepatic IRF9 overexpression in both diet-induced and genetically (ob/ob) obese mice showed markedly improved hepatic insulin sensitivity and attenuated hepatic steatosis and inflammation. We further employed a yeast two-hybrid screening system to investigate the interactions between IRF9 and its cofactors. Importantly, we identified that IRF9
interacts with peroxisome proliferator-activated receptor RGFP966 purchase alpha (PPAR-α), an important metabolism-associated nuclear receptor, to activate PPAR-α target genes. In addition, liver-specific PPAR-α overexpression rescued insulin sensitivity and ameliorated hepatic steatosis and inflammation in IRF9 KO mice. Conclusion: IRF9 attenuates hepatic IR, steatosis, and inflammation through interaction with PPAR-α. (Hepatology 2013;58:603–616) Metabolic disorders, including obesity, nonalcoholic fatty liver disease, metabolic syndrome, and diabetes, are global public health issues and are increasingly severe as the result of an aging population, urbanization, and associated lifestyle changes.[1, 2] Obesity is recognized as a chronic low-grade systemic inflammatory state.[3] In obesity, the inhibitor click here of nuclear factor kappa B kinase beta subunit/nuclear factor kappa B (IKKβ/NFκB) and Jun N-terminal kinase 1/activator protein 1 (JNK1/AP-1) pathways are activated in multiple tissues.[4] Consequently, inflammatory cells infiltrate into adipose tissue. M1-like macrophages secrete proinflammatory cytokines (e.g., tumor necrosis factor alpha [TNF-α] and interleukin [IL]-1β), which impair insulin action.[5, 6] Additionally, ectopic lipid accumulation[7] and endoplasmic reticulum stress[8] may contribute to insulin resistance (IR).
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- 929; 95% CI: 1530-5607; P = 0001), and SH (OR, 2316; 95% CI: