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miRNA-122 Protects Mice and Human Hepatocytes from Acetaminophen Toxicity by Regulating Cytochrome P450 Family 1 Subfamily A Member 2 and Family 2 Subfamily E Member 1 Expression.

Authors
  • Chowdhary, Vivek1
  • Teng, Kun-Yu1
  • Thakral, Sharda1
  • Zhang, Bo2
  • Lin, Cho-Hao1
  • Wani, Nissar3
  • Bruschweiler-Li, Lei4
  • Zhang, Xiaoli5
  • James, Laura6
  • Yang, Dakai7
  • Junge, Norman7
  • Brüschweiler, Rafael8
  • Lee, William M9
  • Ghoshal, Kalpana10
  • 1 Department of Pathology, The Ohio State University, Columbus, Ohio.
  • 2 Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio.
  • 3 Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio.
  • 4 Campus Chemical Instrument Center, The Ohio State University, Columbus, Ohio.
  • 5 Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio.
  • 6 Department of Pediatrics, Arkansas Children's Hospital, Little Rock, Arkansas.
  • 7 Department of Pediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany. , (Germany)
  • 8 Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio; Campus Chemical Instrument Center, The Ohio State University, Columbus, Ohio; Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, Ohio.
  • 9 Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas. Electronic address: [email protected]
  • 10 Department of Pathology, The Ohio State University, Columbus, Ohio. Electronic address: [email protected]
Type
Published Article
Journal
American Journal Of Pathology
Publisher
Elsevier
Publication Date
Dec 01, 2017
Volume
187
Issue
12
Pages
2758–2774
Identifiers
DOI: 10.1016/j.ajpath.2017.08.026
PMID: 28963035
Source
Medline
License
Unknown

Abstract

Acetaminophen toxicity is a leading cause of acute liver failure (ALF). We found that miRNA-122 (miR-122) is down-regulated in liver biopsy specimens of patients with ALF and in acetaminophen-treated mice. A marked decrease in the primary miR-122 expression occurs in mice on acetaminophen overdose because of suppression of its key transactivators, hepatocyte nuclear factor (HNF)-4α and HNF6. More importantly, the mortality rates of male and female liver-specific miR-122 knockout (LKO) mice were significantly higher than control mice when injected i.p. with an acetaminophen dose not lethal to the control. LKO livers exhibited higher basal expression of cytochrome P450 family 2 subfamily E member 1 (CYP2E1) and cytochrome P450 family 1 subfamily A member 2 (CYP1A2) that convert acetaminophen to highly reactive N-acetyl-p-benzoquinone imine. Upregulation of Cyp1a2 primary transcript and mRNA in LKO mice correlated with the elevation of aryl hydrocarbon receptor (AHR) and mediator 1 (MED1), two transactivators of Cyp1a2. Analysis of ChIP-seq data in the ENCODE (Encyclopedia of DNA Element) database identified association of CCCTC-binding factor (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. Pulse-chase studies found that CYP2E1 protein level is upregulated in LKO hepatocytes. Notably, miR-122 depletion sensitized differentiated human HepaRG cells to acetaminophen toxicity that correlated with upregulation of AHR, MED1, and CYP1A2 expression. Collectively, these results reveal a critical role of miR-122 in acetaminophen detoxification and implicate its therapeutic potential in patients with ALF.

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