title: The glucagon-like peptide-1 receptor agonist Exendin 4 has a protective role in ischemic injury of lean and steatotic liver by inhibiting cell death and stimulating lipolysis.
abstract: Nonalcoholic fatty liver disease is an increasingly prevalent spectrum of conditions characterized by excess fat deposition within hepatocytes. Affected hepatocytes are known to be highly susceptible to ischemic insults, responding to injury with increased cell death, and commensurate liver dysfunction. Numerous clinical circumstances lead to hepatic ischemia. Mechanistically, specific means of reducing hepatic vulnerability to ischemia are of increasing clinical importance. In this study, we demonstrate that the glucagon-like peptide-1 receptor agonist Exendin 4 (Ex4) protects hepatocytes from ischemia reperfusion injury by mitigating necrosis and apoptosis. Importantly, this effect is more pronounced in steatotic livers, with significantly reducing cell death and facilitating the initiation of lipolysis. Ex4 treatment leads to increased lipid droplet fission, and phosphorylation of perilipin and hormone sensitive lipase - all hallmarks of lipolysis. Importantly, the protective effects of Ex4 are seen after a short course of perioperative treatment, potentially making this clinically relevant. Thus, we conclude that Ex4 has a role in protecting lean and fatty livers from ischemic injury. The rapidity of the effect and the clinical availability of Ex4 make this an attractive new therapeutic approach for treating fatty livers at the time of an ischemic insult.
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA. narorag@emory.edu
authors.forename: Nitika A
authors.initials: NA
authors.lastname: Gupta
authors.forename: Vasantha L
authors.initials: VL
authors.lastname: Kolachala
authors.forename: Rong
authors.initials: R
authors.lastname: Jiang
authors.forename: Carlos
authors.initials: C
authors.lastname: Abramowsky
authors.forename: Rene
authors.initials: R
authors.lastname: Romero
authors.forename: Nimita
authors.initials: N
authors.lastname: Fifadara
authors.forename: Frank
authors.initials: F
authors.lastname: Anania
authors.forename: Stuart
authors.initials: S
authors.lastname: Knechtle
authors.forename: Allan
authors.initials: A
authors.lastname: Kirk
mesh_terms: D041721:3T3-L1 Cells; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D000077270:Exenatide; D005234:Fatty Liver / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D000067757:Glucagon-Like Peptide-1 Receptor; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008066:Lipolysis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D002787:Sterol Esterase / Q000378:metabolism; D013851:Thinness / Q000150:complications / Q000473:pathology*; D014688:Venoms / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002352:Carrier Proteins; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D000070778:Perilipin-1; D010750:Phosphoproteins; D020011:Protective Agents; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide; D002787:Sterol Esterase