Mfn2 is an integral outer mitochondrial membrane protein. Both the NH2 and COOH-terminal parts are exposed to the cytosol and a small part of Mfn2 presumably faces the intermembrane space, and splits the transmembrane domain into two parts. Although it has been shown that the expression of Mfn2 was down-regulated in liver diseases, the role of Mfn2 in chronic cholestatic liver diseases has not been investigated. In this study, we showed that GCDCA down-regulated Mfn2 expression in patient in vivo and L02 cells in vitro. We hypothesize that the pathogenesis of chronic cholestatic liver diseases are related to mfn2 expression. Mitochondrial morphology is regulated by fusion and fission processes that are controlled by a growing set of “mitochondriashaping” proteins, particularly Mfn2. Mfn2 plays an important role in mitochondria fusion and is critical for mitochondrial function. Growing evidence indicates that increased Mfn2dependent mitochondrial fusion serves to maintain a tubular mitochondrial network and to optimize mitochondrial function. For example, defects in ATP synthesis, whereas the induction of Mfn2 increases glucose oxidation and restores ATP levels. In addition, the ablation of Mfn2 led to a disruption of the mitochondrial network and an increase in ROS production. Our results indicate that Mfn2 overexpression increased mitochondrial fusion, followed by the reversal of mitochondrial dysfunction, such as the reduction of the excess ROS production, reversal of the reduction in ATP levels, and amelioration of the decrease in DYm caused by GCDCAinduced hepatotoxicity. Taken together, these findings suggest that Mfn2-mediated mitochondrial fusion is an essential mechanism underlying GCDCA-induced hepatotoxicity in extrahepatic cholestasis.In this study we examined the expression of HIF-1a protein, a signature hypoxia-related transcription factor upstream of VEGF. We investigated if HIF-1a expression contributes to metalimplant debris induced aseptic inflammation, particularly in cases of elevated exposure to metal implant debris. Both in vitro and in vivo, we examined whether MoM AbMole Folinic acid calcium salt pentahydrate arthroplasty debris preferentially to other metals induces local pathology responses by creating cobalt-induced hypoxic-like responses as evidenced by the production and accumulation of HIF-1a protein and known associated reactions. Collectively, our in vitro and in vivo data support the contention that metal particulate and soluble degradation products can effect local innate immune responses and tissues in a specific pathophysiologic manner where hypoxic microenvironment is produced, evidenced by accumulation of HIF-1a protein. High numbers of macrophages in peri-implant tissues are indicative of aseptic loosening and periprosthetic osteolysis. VEGF is integral to this process and is known to be a downstream target of HIF-1a protein production and is a potent angiogenic factor that is up-regulated by macrophages in a hypoxic environment.