In clinical premalignant and malignant liver disease samples, enhanced IL-1β/interleukin-1 receptor-associated kinase 1 (IRAK-1) signaling accompanied by increased Gankyrin was observed. Lower expression of Gankyrin and phospho-IRAK-1 are favorable prognostic markers for HCC. A similar correlation was observed in the diethylnitrosamine (DEN) model of rat hepatocarcinogenesis. The results from Gankyrin reporter activity, real-time polymerase chain reaction, or immunoblotting further confirmed the up-regulation VX-770 in vivo of Gankyrin by IL-1β/IRAK-1 inflammatory signaling. Moreover, a series of Gankyrin’s truncated reporters were constructed, and electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation

(ChIP) were performed to analyze the properties of Gankyrin promoter. Mechanistically, the core promoter of Gankyrin contains the binding site of nuclear factor Y (NF-Y) family members, which can recruit histone acetyltransferase coactivator E1A-binding protein

p300 (p300) or CREB-binding protein (CBP) to promote Gankyrin transcription. Conversely, knockdown of NF-Y, p300, or CBP inhibits Gankyrin expression. IL-1β stimulation causes sequential phosphorylation of IRAK-1, c-Jun N-terminal kinase (JNK), and p300 and enhances recruitment of the p300/CBP/NF-Y complex to Gankyrin promoter. Inhibition ICG-001 in vivo of phospho-JNK impairs IL-1β/IRAK-1 signaling-mediated up-regulation of Gankyrin. Conclusion: The finding of IL-1β/IRAK-1 signaling promoting Gankyrin expression through JNK and NF-Y/p300/CBP complex provides a fresh view on inflammation-enhanced hepatocarcinogenesis. (Hepatology old 2014) “
“To investigate the efficacy of ezetimibe and lifestyle intervention for treating patients with non-alcoholic fatty liver disease (NAFLD) and residual dyslipidemia via a combination of ezetimibe and lifestyle intervention. Patients with NAFLD with residual dyslipidemia after a 6-month lifestyle intervention program were included. After completion of the 6-month program, the patients received p.o. administration of

ezetimibe at 10 mg/day, in addition to lifestyle intervention, for 6 months. Of the 59 patients with NAFLD who had participated in the 6-month lifestyle intervention program between 2007 and 2012, 21 with residual dyslipidemia (10 males and 11 females) were enrolled. Median age was 58 years (range, 27–75), median bodyweight was 63.0 kg (range, 39.4–109.0), median body mass index was 25.4 kg/m2 (range, 18.2–37.1), median alanine aminotransferase was 23 IU/L (14–73), median high-density lipoprotein (HDL) was 58 mg/dL (range, 37–93), median triglycerides (TG) was 105 mg/dL (range, 42–216) and median low-density lipoprotein (LDL) was 153 (66–209) mg/dL. After 6 months of treatment with ezetimibe, serum LDL levels were improved in 15 of 20 (75%) patients (P = 0.0015), while no improvements were observed in the remaining five patient (25%).