title: Time-dependent network analysis reveals molecular targets underlying the development of diet-induced obesity and non-alcoholic steatohepatitis.
abstract: Prolonged high-fat diet leads to the development of obesity and multiple comorbidities including non-alcoholic steatohepatitis (NASH), but the underlying molecular basis is not fully understood. We combine molecular networks and time course gene expression profiles to reveal the dynamic changes in molecular networks underlying diet-induced obesity and NASH. We also identify hub genes associated with the development of NASH. 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. These networks were associated with cell-to-cell signaling and interaction (Network 1), lipid metabolism (Network 2), hepatic system disease (Network 3 and 5), and inflammatory response (Network 4). When we merged these 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 interrelated 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.
authors.affiliation: Division of Biosystems Research, Green Bio Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 111 Gwahangno, Yuseong-gu, Daejeon, 305-806, Republic of Korea.
authors.forename: Hea-Young
authors.initials: HY
authors.lastname: Oh
authors.forename: Su-Kyung
authors.initials: SK
authors.lastname: Shin
authors.forename: Hyoung-Sam
authors.initials: HS
authors.lastname: Heo
authors.forename: Ji-Sook
authors.initials: JS
authors.lastname: Ahn
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Kwon
authors.forename: Jung Han Yoon
authors.initials: JH
authors.lastname: Park
authors.forename: Yun-Young
authors.initials: YY
authors.lastname: Cho
authors.forename: Hae-Jin
authors.initials: HJ
authors.lastname: Park
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Lee
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Kim
authors.forename: Un-Ju
authors.initials: UJ
authors.lastname: Jung
authors.forename: Robin A
authors.initials: RA
authors.lastname: McGregor
authors.forename: Cheol-Goo
authors.initials: CG
authors.lastname: Hur
authors.forename: Myung-Sook
authors.initials: MS
authors.lastname: Choi