title: mTOR activation protects liver from ischemia/reperfusion-induced injury through NF-κB pathway.
abstract: Hepatic steatosis renders liver more vulnerable to ischemia/reperfusion injury (IRI), which commonly occurs in transplantation, trauma, and liver resection. The underlying mechanism is not fully characterized. We aimed to clarify the role of mechanistic target of rapamycin (mTOR) signaling in hepatic ischemia/reperfusion injury (HIRI) in normal and steatotic liver usingAlb-TSC1-/-(AT) andAlb-mTOR-/-(Am) transgenic mice. Steatotic liver induced by high-fat diet was more vulnerable to IRI. Activation of hepatic mTOR in AT mice decreased lipid accumulation attenuated HIRI as measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, circulating levels of alanine aminotransferase and lactate dehydrogenase, and inflammatory mediators such as monocyte chemoattractant protein 1 (MCP-1), TNF-α, and IL-6 and hepatic cleaved caspase 3 in mice fed either a normal chow diet or a high-fat diet. The effects of mTOR activation on hepatic cleaved caspase 3 were reversed by rapamycin, an inhibitor of mTOR signaling. Inhibition of hepatic mTOR in Am mice increased hepatic lipid deposition and HIRI. The increment in hepatic susceptibility to IRI was significantly attenuated by pretreatment with IKKβ inhibitor. Further, suppression of mTOR facilitated nuclear translocation of NF-κB p65. In conclusion, our study suggests that mTOR activity in hepatocytes decreases hepatic vulnerability to injury through a mechanism dependent on NF-κB proinflammatory cytokine signaling pathway in both normal and steatotic liver.-Li, Z., Zhang, J., Mulholland, M., Zhang, W. mTOR activation protects liver from ischemia/reperfusion-induced injury through NF-κB pathway.
authors.affiliation: Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
authors.forename: Ziru
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA micham@umich.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Mulholland
authors.affiliation: Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA weizhenz@umich.edu.|Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
authors.forename: Weizhen
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000139:chemically induced / Q000150:complications*; D005786:Gene Expression Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D051550:I-kappa B Kinase / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000517:prevention & control*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051996:Transcription Factor RelA; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase
keywords: IKKβ; TSC1; hepatic steatosis; nuclear translocation