Impact of intracellular glyceraldehyde-derived advanced glycation end-products on human hepatocyte cell death

Akiko Sakasai-Sakai,Jun-ichi Takino,Masayoshi Takeuchi,Takanobu Takata

doi:10.1038/s41598-017-14711-3

Abstract

Hepatocyte cell death is a key feature of nonalcoholic steatohepatitis (NASH); however, the pathogenesis of NASH currently remains unclear. We aimed to investigate the effects of intracellular glyceraldehyde (GA)-derived advanced glycation end-products (GA-AGEs) on human hepatocyte cell death. The accumulation of intracellular GA-AGEs has been associated with the induction of DNA damage and hepatocyte necrotic cell death. Among intracellular GA-AGEs, caspase-3 has been identified as a GA-AGE-modified protein with abrogated protein function. Furthermore, the activation of caspase-3 and induction of hepatocyte apoptosis by camptothecin, a DNA-damaging agent, was suppressed by a treatment with GA. These results suggest the inhibitory effects of GA-AGE-modified caspase-3 on the induction of DNA-damage-induced apoptosis, which is associated with hepatocyte necrosis. Therefore, the suppression of necrosis, the inflammatory form of cell death, by the accumulation of GA-AGEs and GA-AGE-modified caspase-3 may represent a novel therapeutic target for the pathogenesis of NASH.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is currently the most common feature of chronic liver disease
GA-advanced glycation end-products (AGEs) are expected to mainly accumulate in hepatocytes because fructose metabolism mostly occurs in the liver
We previously reported that the treatment of the human hepatocellular carcinoma (HCC) cell line Hep3B with GA or high doses of fructose resulted in the accumulation of GA-derived AGEs (GA-AGEs) in these cells, and identified heat shock cognate 70 (Hsc70) or heterogeneous nuclear ribonucleoprotein M as a GA-AGE-modified protein[19,20]

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is currently the most common feature of chronic liver disease. We previously reported that the treatment of the human hepatocellular carcinoma (HCC) cell line Hep3B with GA or high doses of fructose resulted in the accumulation of GA-AGEs in these cells, and identified heat shock cognate 70 (Hsc70) or heterogeneous nuclear ribonucleoprotein M (hnRNPM) as a GA-AGE-modified protein[19,20]. In addition to the accumulation of GA-AGEs, the mRNA of the inflammatory marker C-reactive protein (CRP) was significantly increased in Hep3B cells by a treatment with GA19 These findings suggest that the accumulation of GA-AGE-modified intracellular proteins causes cellular dysfunction and induces inflammatory responses. The cell death type and mechanisms induced by the accumulation of GA-AGEs in hepatocytes, which we proposed as one of the causes of NASH, currently remain unclear. We investigated the cell death type and mechanisms induced by the accumulation of intracellular GA-AGEs in human hepatocytes, and identified GA-AGE-modified proteins. Our results provide novel insights into cell death associated with NASH, which has potential as a therapeutic anti-inflammation target for the treatment of NASH

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