title: Mitigation of autophagy ameliorates hepatocellular damage following ischemia-reperfusion injury in murine steatotic liver.
abstract: Ischemia-reperfusion injury (IRI) is a common clinical consequence of hepatic surgery, cardiogenic shock, and liver transplantation. A steatotic liver is particularly vulnerable to IRI, responding with extensive hepatocellular injury. Autophagy, a lysosomal pathway balancing cell survival and cell death, is engaged in IRI, although its role in IRI of a steatotic liver is unclear. The role of autophagy was investigated in high-fat diet (HFD)-fed mice exposed to IRI in vivo and in steatotic hepatocytes exposed to hypoxic IRI (HIRI) in vitro. Two inhibitors of autophagy, 3-methyladenine and bafilomycin A1, protected the steatotic hepatocytes from HIRI. Exendin 4 (Ex4), a glucagon-like peptide 1 analog, also led to suppression of autophagy, as evidenced by decreased autophagy-associated proteins [microtubule-associated protein 1A/1B-light chain 3 (LC3) II, p62, high-mobility group protein B1, beclin-1, and autophagy-related protein 7], reduced hepatocellular damage, and improved mitochondrial structure and function in HFD-fed mice exposed to IRI. Decreased autophagy was further demonstrated by reversal of a punctate pattern of LC3 and decreased autophagic flux after IRI in HFD-fed mice. Under the same conditions, the effects of Ex4 were reversed by the competitive antagonist exendin 9-39. The present study suggests that, in IRI of hepatic steatosis, treatment of hepatocytes with Ex4 mitigates autophagy, ameliorates hepatocellular injury, and preserves mitochondrial integrity. These data suggest that therapies targeting autophagy, by Ex4 treatment in particular, may ameliorate the effects of IRI in highly prevalent steatotic liver.
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia; Transplant Services, Children's Healthcare of Atlanta, Atlanta, Georgia; narorag@emory.edu.
authors.forename: Nitika A
authors.initials: NA
authors.lastname: Gupta
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: Vasantha L
authors.initials: VL
authors.lastname: Kolachala
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: Rong
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia; Department of Pathology, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: Carlos
authors.initials: C
authors.lastname: Abramowsky
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia; Transplant Services, Children's Healthcare of Atlanta, Atlanta, Georgia;
authors.forename: Asha
authors.initials: A
authors.lastname: Shenoi
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: Astrid
authors.initials: A
authors.lastname: Kosters
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: Haritha
authors.initials: H
authors.lastname: Pavuluri
authors.affiliation: Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and.
authors.forename: Frank
authors.initials: F
authors.lastname: Anania
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia; Transplant Services, Children's Healthcare of Atlanta, Atlanta, Georgia; Department of Surgery, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Allan D
authors.initials: AD
authors.lastname: Kirk
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D000077270:Exenatide; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000201:enzymology; D065626:Non-alcoholic Fatty Liver Disease / Q000473:pathology*; D010455:Peptides / Q000494:pharmacology; D015427:Reperfusion Injury / Q000473:pathology* / Q000517:prevention & control*; D014688:Venoms / Q000494:pharmacology
chemical_list: D018942:Macrolides; D010455:Peptides; D014688:Venoms; C025946:3-methyladenine; C040929:bafilomycin A1; D000077270:Exenatide; D000225:Adenine
keywords: autophagy; ischemia-reperfusion injury; steatosis