J Cell Commun Signal. 2017 Dec 6. doi: 10.1007/s12079-017-0432-4. [Epub ahead of print]
Wu, W; Hu, X; Zhou, X; Klenotic, PA; Zhou, Q; Lin, Z
Case Western Reserve University School of Medicine, Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, 2103 Cornell Road, Room 4-541, Cleveland, OH, 44106, USA. Tongji Hospital, Tongji Medical College, Huazhong University o
Non-alcoholic fatty liver disease (NAFLD) is a condition in which fat accumulates in the liver of patients without a prior history of alcohol abuse. The most severe form, nonalcoholic steatohepatitis (NASH), often leads to hepatic fibrosis and cirrhosis with ensuing complications. To date, there is no pharmacologic treatment for NASH. The biological effects of CCN3, specifically its role in the regulation of inflammation, reactive oxygen species production and angiogenesis, have been recently established. Additional data suggests that CCN3 is associated with the development of tumors in the liver yet may be protective of liver fibrogenesis. Currently, the role of CCN3 in NAFLD/NASH remains unexplored. Therefore, the objective of our investigation was to decipher the role of myeloid-deficient CCN3 in the pathogenesis of NASH and the underlying mechanisms of CCN3 in modulation of hepatic function. Wild type and myeloid CCN3-deficient mice were fed a methionine- and choline-deficient diet to induced NASH. Increased lipid, cholesterol, and cholesterol ester accumulation was observed in myeloid CCN3-deficient mice when compared to the control group. This disease state was associated with alterations of key genes involved in lipid synthesis, β-oxidation and lipid uptake. Additionally, the levels of important molecules critical for inflammation, ROS generation, ER stress and liver injury were significantly elevated; as was the observed severity of hepatic apoptosis and necroptosis. Therefore, CCN3 is critical for protection from hepatic apoptosis and necroptosis in our induced NASH model and our findings suggest that CCN3 can be exploited as a therapeutic target for the treatment of NASH.
The team at Ozgene has over two decades of experience creating customised knockout and knock-in mice for pivotal medical research globally. Over 400 scientific publications are based on research using Ozgene mice.