title: Mutant p53 in concert with an interleukin-27 receptor alpha deficiency causes spontaneous liver inflammation, fibrosis, and steatosis in mice.
abstract: The cellular and molecular etiology of unresolved chronic liver inflammation remains obscure. Whereas mutant p53 has gain-of-function properties in tumors, the role of this protein in liver inflammation is unknown. Herein, mutant p53(R172H) is mechanistically linked to spontaneous and sustained liver inflammation and steatosis when combined with the absence of interleukin-27 (IL27) signaling (IL27RA), resembling the phenotype observed in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) patients. Indeed, these mice develop, with age, hepatocyte necrosis, immune cell infiltration, fibrosis, and micro- and macrosteatosis; however, these phenotypes are absent in mutant p53(R172H) or IL27RA(-/-) mice. Mechanistically, endothelin A receptor (ETAR)-positive macrophages are highly accumulated in the inflamed liver, and chemical inhibition of ETAR signaling reverses the observed phenotype and negatively regulates mutant p53 levels in macrophages.
  
  
  CONCLUSIONS
  The combination of mutant p53 and IL27RA(-/-) causes spontaneous liver inflammation, steatosis, and fibrosis in vivo, whereas either gene alone in vivo has no effects on the liver.
authors.affiliation: Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Denada
authors.initials: D
authors.lastname: Dibra
authors.affiliation: Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Xia
authors.affiliation: Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Abhisek
authors.initials: A
authors.lastname: Mitra
authors.affiliation: Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jeffry J
authors.initials: JJ
authors.lastname: Cutrera
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
authors.affiliation: Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Shulin
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D016158:Genes, p53; D008264:Macrophages / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000172:deficiency*; D018123:Receptors, Interleukin
chemical_list: C484747:Il27ra protein, mouse; D044022:Receptor, Endothelin A; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin