title: Inhibition of Dexamethasone-induced Fatty Liver Development by Reducing miR-17-5p Levels.
abstract: Steatosis is a pivotal event in the initiation and progression of nonalcoholic fatty liver disease (NAFLD) which can be driven by peroxisome proliferator-activated receptor-α (PPAR-α) dysregulation. Through examining the effect of PPAR-α on fatty liver development, we found that PPAR-α is a target of miR-17-5p. Transgenic mice expressing miR-17 developed fatty liver and produced higher levels of triglyceride and cholesterol but lower levels of PPAR-α. Ectopic expression of miR-17 enhanced cellular steatosis. Gain-of-function and loss-of-function experiments confirmed PPAR-α as a target of miR-17-5p. On the other hand, PPAR-α bound to the promoter of miR-17 and promoted its expression. The feed-back loop between miR-17-5p and PPAR-α played a key role in the induction of steatosis and fatty liver development. Mice with high levels of miR-17-5p were sensitive to Dexamethasone-induced fatty liver formation. Inhibition of miR-17-5p suppressed this process and enhanced PPAR-α expression in mice treated with Dexamethasone. Clofibrate, Ciprofibrate, and WY-14643: three agents used for treatment of metabolic disorders, were found to promote PPAR-α expression while decreasing miR-17-5p levels and inhibiting steatosis. Our studies show that miR-17-5p inhibitor and agents used in metabolic disorders may be applied in combination with Dexamethasone in the treatment of anti-inflammation, immunosuppression, and cancer patients.
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: William W
authors.initials: WW
authors.lastname: Du
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; School of Public Health, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Fengqiong
authors.initials: F
authors.lastname: Liu
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sze Wan
authors.initials: SW
authors.lastname: Shan
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Xindi Cindy
authors.initials: XC
authors.lastname: Ma
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Shaan
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Tianru
authors.initials: T
authors.lastname: Jin
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Spaner
authors.affiliation: Department of Chemistry and Centre for Research on Biomolecular Interactions, York University, Toronto, Ontario, Canada.
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Krylov
authors.affiliation: Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen, P.R. China.
authors.forename: Yaou
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Public Health, Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Ling
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Electronic address: byang@sri.utoronto.ca.
authors.forename: Burton B
authors.initials: BB
authors.lastname: Yang
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D003907:Dexamethasone / Q000633:toxicity; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D047493:PPAR alpha / Q000096:biosynthesis* / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; D047493:PPAR alpha; D014280:Triglycerides; D003907:Dexamethasone; D002784:Cholesterol