TRAIL deletion prevents liver inflammation but not adipose tissue inflammation during murine diet-induced obesity

Petra Hirsova, Peggy Weng, Warda Salim, Steven F. Bronk, Thomas S. Griffith, Samar H. Ibrahim, Gregory J. Gores

Research output: Contribution to journalArticlepeer-review


Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its cognate receptor(s) are up-regulated in human and murine nonalcoholic steatohepatitis (NASH); however, the consequence of this enhanced expression on NASH pathogenesis remains unclear. TRAIL may either accentuate liver injury by promoting hepatic steatosis and inflammation or it may mitigate the disease process by improving systemic insulin resistance and averting hepatic fibrosis. Herein, we investigated the role of TRAIL in an obesity-induced murine model of NASH. C57BL/6 wild-type mice and Trail–/– mice were placed on a 20-week standard chow or a high-fat, high-fructose, and high-cholesterol (FFC) diet, which induces obesity, insulin resistance, and NASH. Metabolic phenotype, liver injury, inflammation and fibrosis, and adipose tissue homeostasis were examined. FFC diet-fed Trail–/– mice displayed no difference in weight gain and metabolic profile when compared to wild-type mice on the same diet. All FFC-fed mice developed significant hepatic steatosis, which was attenuated in Trail–/– mice. TRAIL deficiency also significantly decreased FFC diet-induced liver injury as manifested by reduced serum alanine aminotransferase values, hepatic terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive cells, and macrophage-associated inflammation. FFC diet-associated hepatic stellate cell activation and hepatic collagen deposition were also abrogated in Trail–/– mice. In contrast to the liver, TRAIL deletion did not improve FFC diet-induced adipose tissue injury and inflammation and actually aggravated insulin resistance. Conclusion: NASH pathogenesis may be dissociated from other features of the metabolic syndrome, and liver-targeted inhibition of TRAIL signaling may be salutary. (Hepatology Communications 2017;1:648–662).

Original languageEnglish (US)
Pages (from-to)648-662
Number of pages15
JournalHepatology Communications
Issue number7
StatePublished - Sep 2017

ASJC Scopus subject areas

  • Hepatology


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