1. Academic Validation
  2. A Novel AKT Activator, SC79, Prevents Acute Hepatic Failure Induced by Fas-Mediated Apoptosis of Hepatocytes

A Novel AKT Activator, SC79, Prevents Acute Hepatic Failure Induced by Fas-Mediated Apoptosis of Hepatocytes

  • Am J Pathol. 2018 May;188(5):1171-1182. doi: 10.1016/j.ajpath.2018.01.013.
Wei Liu 1 Zhen-Tang Jing 2 Shu-Xiang Wu 1 Yun He 1 Yan-Ting Lin 1 Wan-Nan Chen 2 Xin-Jian Lin 1 Xu Lin 3
Affiliations

Affiliations

  • 1 Key Laboratory of the Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
  • 2 Key Laboratory of the Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China.
  • 3 Key Laboratory of the Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China. Electronic address: linxu@mail.fjmu.edu.cn.
Abstract

Acute liver failure is a serious clinical problem of which the underlying pathogenesis remains unclear and for which effective therapies are lacking. The Fas Receptor/ligand system, which is negatively regulated by Akt, is known to play a prominent role in hepatocytic cell death. We hypothesized that Akt activation may represent a strategy to alleviate Fas-induced fulminant liver failure. We report here that a novel Akt Activator, SC79, protects hepatocytes from Apoptosis induced by agonistic anti-Fas antibody CH11 (for humans) or Jo2 (for mice) and significantly prolongs the survival of mice given a lethal dose of Jo2. Under Fas-signaling stimulation, SC79 inhibited Fas aggregation, prevented the recruitment of the adaptor molecule Fas-associated death domain (FADD) and procaspase-8 [or FADD-like IL-1β-converting Enzyme (FLICE)] into the death-inducing signaling complex (DISC), but SC79 enhanced the recruitment of the long and short isoforms of cellular FLICE-inhibitory protein at the DISC. All of the SC79-induced hepatoprotective and DISC-interruptive effects were confirmed to have been reversed by the Akt Inhibitor LY294002. These results strongly indicate that SC79 protects hepatocytes from Fas-induced fatal hepatic Apoptosis. The potent alleviation of Fas-mediated hepatotoxicity by the relatively safe drug SC79 highlights the potential of our findings for immediate hepatoprotective translation.

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