Targeting hepatic TRAF1-ASK1 signaling to improve inflammation, insulin resistance, and hepatic steatosis.

BACKGROUND & AIMS: Tumor necrosis factor receptor-associated factor 1 (TRAF1) is an important adapter protein that is largely implicated in molecular events regulating immunity/inflammation and cell death. Although inflammation is closely related to and forms a vicious circle with insulin dysfunction and hepatic lipid accumulation, the role of TRAF1 in hepatic steatosis and the related metabolic disorders remains unclear. METHODS: The participation of TRAF1 in the initiation and progression of hepatic steatosis was evaluated in high fat diet (HFD)-induced and genetic obesity. Mice with global TRAF1 knockout or liver-specific TRAF1 overexpression were employed to investigate the role of TRAF1 in insulin resistance, inflammation, and hepatic steatosis based on various phenotypic examinations. Molecular mechanisms underlying TRAF1-regulated hepatic steatosis were further explored in vivo and in vitro. RESULTS: TRAF1 expression was significantly upregulated in the livers of NAFLD patients and obese mice and in palmitate-treated hepatocytes. In response to HFD administration or in ob/ob mice, TRAF1 deficiency was hepatoprotective, whereas the overexpression of TRAF1 in hepatocytes contributed to the pathological development of insulin resistance, inflammatory response and hepatic steatosis. Mechanistically, hepatocyte TRAF1 promotes hepatic steatosis through enhancing the activation of ASK1-mediated P38/JNK cascades, as evidenced by the fact that ASK1 inhibition abolished the exacerbated effect of TRAF1 on insulin dysfunction, inflammation, and hepatic lipid accumulation. CONCLUSIONS: TRAF1 functions as a positive regulator of insulin resistance, inflammation, and hepatic steatosis dependent on the activation of ASK1-P38/JNK axis.

Polymorphisms of the PRNP gene in Chinese populations and the identification of a novel insertion mutation.

The two common polymorphisms (385A > G: M129V and 655G > A: E219 K) in the human prion gene (PRNP) play important roles in the pathogenesis of Creutzfeldt-Jakob diseases. We screened a total of 626 individuals, who represent three ethnic populations of China, Han, Hui, and Uyghur, for the two polymorphisms. The frequencies of M/M homozygote at residue 129 in these three groups differ significantly. The Han has a much higher frequency (98%) than Hui (85%) and Uyghur (60%). On the other hand, the frequencies of the E/E at residue 219 are higher in Uyghur (98%) and Hui (96%) than in Han (90%). We also investigated two other less common variants of PRNP, a silent substitution at residue 117 (351A > G: A117A), and one octapeptide-repeat deletion (1-OPRD) in the octapeptide-coding region. We found three Uyghur individuals with silent substitution at residue 117. Four Hui (2.0%) and one Han (0.5%) donors were found to be heterozygous for 1-OPRD. A novel three extra-repeat (72 bp) insertion within the octapeptide-coding region was identified in one healthy 11-years-old Hui. Identical mutation was also found in her mother but not her father.