Network Meta-analysis on the Molecular Mechanisms of Palmitic Acid in Liver Fibrosis

Author(s): Myeong Gil Jun, Heping Zhou

Elevated levels of free fatty acids have been suggested as the main factors contributing to the development of non-alcoholic steatohepatitis. This study conducted network meta-analysis using the QIAGEN Ingenuity Pathway Analysis (IPA) to examine the roles of saturated fatty acids (SFAs) and n-3 unsaturated fatty acids (UFAs) in the activation of Hepatic Fibrosis Signaling Pathway and collagen accumulation. Our analysis identified the shortest paths from palmitic acid (PA), a SFA, to the Hepatic Fibrosis Signaling Pathway, and found that elevated level of PA may increase the activities of transcription factors, such as CEBPβ, JUN/FOS, NFκB, and PPARγ, cytokines/chemokines/growth factors, such as TNF, IL1, CCL2, CCN2, LEP, and TGFβ1, oxidative stress mediators, such as NOX, and fibrinolysis regulators, such as SERPINE1, which may in turn activate the Hepatic Fibrosis Signaling Pathway. Our analysis also identified the shortest paths from PA to collagen accumulation and found that elevated level of PA may increase the activities of signaling mediators, such as ERK1/2, cytokines/chemokines/growth factors, such as TNF, IL6, CCL2, CCN2, LEP, and TGFβ1, which may in turn increase the accumulation of collagens. In contrast, the increased levels of n-3 UFAs inhibited the activities of PDGFA, PDGFB, TNF, IL1, and CCL2. Our analysis also identified seven PA- and liver fibrosis-associated molecules mapped to the shortest paths from PA the Hepatic Fibrosis Signaling Pathway and from PA to collagens. Mapping of these seven molecules, TNF, IL1A, CCL2, TGFβ1, CCN2, LEP, and SERPINE1, to the Hepatic Fibrosis Signaling Pathway showed that these molecules may lead to proinflammatory response in the liver, reduced ECM degradation, and enhanced ECM accumulation. Our studies shed light on the molecular mechanisms by which PA contributes to liver fibrosis and the key mediating molecules that may be used for further research and