Time-dependent network analysis reveals molecular targets underying the development of diet-induced obesity and non-alcoholic steatohepatitis.

Core diet-induced obesity networks were constructed using Ingenuity pathway analysis (IPA) based on 332 high-fat diet responsive genes identified in liver by time-course microarray analysis (8 time-points over 24 weeks) of high-fat diet fed mice compared to normal diet fed mice. IPA identified five core diet-induced obesity networks with time-dependent gene expression changes in liver. When we merged core diet-induced obesity networks, Tlr2, Cd14 and Ccnd1 emerged as hub genes associated with both liver steatosis and inflammation and were altered in a time-dependent manner. Further protein-protein interaction network analysis revealed Tlr2, Cd14 and Ccnd1 were inter-related through the ErbB/insulin signaling pathway. Dynamic changes occur in molecular networks underlying diet-induced obesity. Tlr2, Cd14 and Ccnd1 appear to be hub genes integrating molecular interactions associated with the development of NASH. Therapeutics targeting hub genes and core diet-induced obesity networks may help ameliorate diet-induced obesity and NASH.

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Oh HY, Shin SK, Heo HS, Ahn JS, Kwon EY, Park JH, Cho YY, Park HJ, Lee MK, Kim EJ, Jung UJ, McGregor RA, Hur CG, Choi MS