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High Glucose limits Autophagy via inhibition of Nuclear Translocation of Transcription Factor EB
Author(s) -
Kramer Benjamin,
Kobayashi Satoru,
Gerdes Martin,
Liang Qiangrong
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1273.7
Subject(s) - tfeb , autophagy , microbiology and biotechnology , lysosome , programmed cell death , transcription factor , biology , chemistry , biochemistry , apoptosis , gene , enzyme
Cardiovascular disease is the major consequence resulting in morbidity and mortality amongst diabetic patients. Hyperglycemia is a known independent risk factor associated with diabetic heart failure. However, the mechanisms that mediate hyperglycemia‐induced cardiac damage remain poorly understood. Previous literatures show that generation of reactive oxygen species (ROS) and lack of cell maintenance compromise cellular sustainability. Autophagy is the principle pathway that maintains cellular homeostasis via lysosomal degradation of proteins and organelles. We previously showed that the inhibition of autophagy is a protective response in hyperglycemia‐induced cardiac injury. Transcription Factor EB (TFEB), known as a master regulator of autophagy‐lysosome pathway, controls the expression of autophagy‐related proteins and lysosomal proteins. In the present study, we determined if high levels of glucose could affect the expression and the nuclear localization of TFEB, and thus autophagic activity, in cultured cardiac cells. Western blotting results suggest that the total protein expression level of TFEB remains consistent under both high (30mM) and physiologic (5.5mM) glucose conditions. However, the nuclear localization of TFEB is markedly reduced in cardiac myocytes cultured under high glucose as shown by immunofluorescence staining and confocal microscopy, indicating that high glucose inhibits the nuclear translocation of TFEB. In addition, the inhibition of TFEB nuclear localization is accompanied by a reduction of lysosomal associated membrane protein 1 (LAMP‐1), suggesting a reduced autophagy‐lysosome activity. Indeed, we show that high glucose inhibits autophagy and induces cell death. However, restoration of autophagic activity by Rapamycin, a known inducer of autophagy, exacerbates high glucose‐induced cell death, suggesting that the inhibition of autophagy is an adaptive response that protects against high glucose toxicity. Interestingly, Rapamycin treatment increases the nuclear translocation of TFEB as shown by increased co‐localization of TFEB and DAPI, a DNA dye that stains nuclei. Rapamycin also reverses the expression level of LAMP‐1. Collectively, our findings suggest that high glucose conditions suppress the nuclear translocation of TFEB, which may be responsible for the protective role of inhibited autophagy in hyperglycemia‐induced cardiac injury. Future studies are warranted to investigate the molecular mechanism that inhibits nuclear translocation of TFEB in high glucose and to determine whether TFEB overexpression or knockdown can regulate autophagic activity, thereby affecting hyperglycemia‐induced cardiac injury.