Abstract
Mice with hepatocyte-specific deletion of autophagy-related 7 (Atg7ΔHep mice) develop hepatoma, suggesting that autophagy deficiency could be a factor in the initiation of tumorigenesis. We have shown that FGF21 is induced as a ‘mitokine’ when Atg7 is disrupted in insulin target tissues such as the liver, which could affect systemic metabolism through endocrine activity. Since FGF21 or other endocrine FGF such as FGF19 can affect tumor growth, we hypothesized that FGF21 produced by Atg7-knockout (KO) hepatocytes may affect the behavior of Atg7-KO hepatoma in an autocrine manner. We, thus, crossed Atg7ΔHep mice with systemic Fgf21-KO (Fgf21−/−) mice to generate Atg7ΔHepFgf21−/− mice. The number and size of hepatoma of Atg7ΔHep mice were significantly increased by additional Fgf21 KO. The proliferation of Atg7-KO hepatocyte was significantly increased by Fgf21 KO. pYAP1/YAP1 representing YAP1 degradation was significantly decreased in the liver of Atg7ΔHepFgf21−/− mice compared to Atg7ΔHepFgf21+/+ mice. Consistently, expression of YAP1/TAZ downstream genes was significantly increased in the liver of Atg7ΔHepFgf21−/− mice compared to Atg7ΔHepFgf21+/+ mice, which could explain the increased size of hepatoma in Atg7ΔHepFgf21−/− mice. Accumulation of ROS and ROS-mediated DNA damage were increased in the liver of Atg7ΔHepFgf21+/+ mice, which was further aggravated by additional Fgf21 KO probably due to the absence of positive effect of FGF21 on mitochondrial function, explaining the increased number of hepatoma in Atg7ΔHepFgf21−/− mice compared to Atg7ΔHepFgf21+/+ mice. These results show that FGF21 produced by autophagy-deficient hepatocytes could have autocrine or paracrine effects on the number and proliferation of autophagy-deficient hepatoma, suggesting that hormones or factors released from autophagy-deficient tumors can influence the behavior or prognosis of the tumor in addition to the effects on host metabolism.
Highlights
Macroautophagy/autophagy as a cellular process involving lysosomal degradation of the own material of the cell through autophagosome formation [1] is critical for the maintenance of organelle function and metabolic homeostasis [2]
Since fibroblast growth factor 21 (FGF21) is produced by autophagy-related 7 (Atg7)-knockout (KO) hepatocytes and FGF21 could have significant impacts on metabolic profile, we first studied metabolic features of Atg7DHepFgf21+/+ and Atg7DHepFgf21−/− mice that were generated by crossing Atg7DHepFgf21+/+ mice with Atg7F/FFgf21−/− mice
Reduced area under the curve (AUC) of Glucose Tolerance Test (GTT) curves in Atg7DHepFgf21+/+ mice on chow diet was abrogated by additional KO of Fgf21, consistent with a previous paper showing the effect of FGF21 release from Atg7-deficient insulin target tissues enhancing glucose tolerance, in high-fat diet fed condition [11] (Supplementary Figure S1E)
Summary
Macroautophagy/autophagy as a cellular process involving lysosomal degradation of the own material of the cell through autophagosome formation [1] is critical for the maintenance of organelle function and metabolic homeostasis [2]. Because of such critical function of autophagy, dysregulated autophagy has been incriminated as a pathogenic factor in the development of diverse diseases such as neurodegenerative diseases, metabolic diseases, cardiovascular disease, and cancer. Regarding the molecular mechanisms of tumor development in autophagy-deficient liver, the roles of genomic damage, accumulation of SQSTM1/p62, an autophagy receptor, inducing activation of KEAP1–NRF2 axis and stabilization of yes-associated protein 1 (YAP1), an effector of the Hippo pathway, have been reported [8–10]
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