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Role of miR-122 in Acetaminophen Induced Liver Injury.

Chowdhary, Vivek K
http://orcid.org/0000-0003-1277-0128
http://rave.ohiolink.edu/etdc/view?acc_num=osu1494133473685399

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Acetaminophen (APAP) toxicity is a major cause of acute liver failure (ALF). Although circulating miR-122 is a sensitive biomarker of ALF, the role of this most abundant liver-specific miRNA in ALF has not been elucidated. Here, we show that miR-122 is downregulated in liver biopsies of ALF patients compared to non-ALF biopsies and in the livers of mice treated with APAP. A dramatic decrease in the primary-miR-122 expression occurs upon APAP overdose in mice due to suppression of its two key trans-activators, HNF4a and HNF6. More importantly, the mortality rates of both male and female liver-specific miR-122 knockout (LKO) (Mir122loxP/loxP; Alb-Cre) mice were significantly higher than that of the age- and sex-matched control (Mir122loxP/loxP) mice when injected intraperitoneally with a dose of APAP lethal to LKO mice. Higher basal levels of CYP2E1 and CYP1A2 that convert APAP to highly reactive N-acetyl-p-benzoquinone imine (NAPQI) are contributing factors to the sensitivity of LKO mice to APAP overdose. Upregulation of Cyp1a2 primary transcript and mRNA in LKO livers correlated with elevation of Ahr and Med1, two trans-activators of Cyp1a2 gene. Analysis of ChIP-seq data in the ENCODE database identified the association of CTCF with Ahr promoter in mouse livers. Both MED1 and CTCF are validated conserved miR-122 targets. Furthermore, depletion of Ahr, Med1 or Ctcf in Mir122-/- hepatocytes reduced Cyp1a2 expression. Glycerol density gradient centrifugation and pulse-chase studies showed that Cyp2e1 is upregulated in LKO hepatocytes at the protein level. Notably, miR-122 depletion sensitized differentiated human HepaRG cells to APAP toxicity that correlated with upregulation of AHR, MED1 and CYP1A2 expression. Collectively, these results suggest a critical role of miR-122 in acetaminophen detoxification and implicate its therapeutic potential in ALF. Cyp1a2 expression. Glycerol density gradient centrifugation and pulse-chase studies showed that Cyp2e1 is upregulated in LKO hepatocytes at the protein level. Notably, miR-122 depletion sensitized differentiated human HepaRG cells to APAP toxicity that correlated with upregulation of AHR, MED1 and CYP1A2 expression. Collectively, these results suggest a critical role of miR-122 in acetaminophen detoxification and implicate its therapeutic potential in ALF.
Kalpana Ghoshal (Advisor)
Samson Jacob (Committee Member)
Tsonwin Hai (Committee Chair)
Ramesh Ganju (Committee Member)
130 p.
Biomedical Research; Molecular Biology
miR-122, DILI, APAP, Acetaminophen, CTCF, MED1, AHR, CYP1A2

Recommended Citations

Citations

  • Chowdhary, V. K. (2017). Role of miR-122 in Acetaminophen Induced Liver Injury. [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1494133473685399

    APA Style (7th edition)

  • Chowdhary, Vivek. Role of miR-122 in Acetaminophen Induced Liver Injury. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1494133473685399.

    MLA Style (8th edition)

  • Chowdhary, Vivek. "Role of miR-122 in Acetaminophen Induced Liver Injury." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1494133473685399

    Chicago Manual of Style (17th edition)

osu1494133473685399
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© 2017, some rights reserved.Creative Commons License Role of miR-122 in Acetaminophen Induced Liver Injury. by Vivek K Chowdhary is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.