mTOR controls ChREBP transcriptional activity and pancreatic β cell survival under diabetic stress

Gia Cac Chau; Dong Uk Im; Tong Mook Kang; Jeong Mo Bae; Won Kim; Suhkneung Pyo; Eun-Yi Moon; Sung Hee Um

doi:10.1083/jcb.201701085

mTOR controls ChREBP transcriptional activity and pancreatic β cell survival under diabetic stress

J Cell Biol. 2017 Jul 3;216(7):2091-2105. doi: 10.1083/jcb.201701085. Epub 2017 Jun 12.

Authors

Gia Cac Chau¹, Dong Uk Im², Tong Mook Kang³, Jeong Mo Bae⁴, Won Kim⁵, Suhkneung Pyo⁶, Eun-Yi Moon⁷, Sung Hee Um^{8

2}

Affiliations

¹ Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, Korea.
² Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea.
³ Department of Physiology, Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, Korea.
⁴ Department of Pathology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea.
⁵ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea.
⁶ School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea.
⁷ Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea [email protected].
⁸ Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, Korea [email protected].

Abstract

Impaired nutrient sensing and dysregulated glucose homeostasis are common in diabetes. However, how nutrient-sensitive signaling components control glucose homeostasis and β cell survival under diabetic stress is not well understood. Here, we show that mice lacking the core nutrient-sensitive signaling component mammalian target of rapamycin (mTOR) in β cells exhibit reduced β cell mass and smaller islets. mTOR deficiency leads to a severe reduction in β cell survival and increased mitochondrial oxidative stress in chemical-induced diabetes. Mechanistically, we find that mTOR associates with the carbohydrate-response element-binding protein (ChREBP)-Max-like protein complex and inhibits its transcriptional activity, leading to decreased expression of thioredoxin-interacting protein (TXNIP), a potent inducer of β cell death and oxidative stress. Consistent with this, the levels of TXNIP and ChREBP were highly elevated in human diabetic islets and mTOR-deficient mouse islets. Thus, our results suggest that a nutrient-sensitive mTOR-regulated transcriptional network could be a novel target to improve β cell survival and glucose homeostasis in diabetes.

MeSH terms

Adult
Aged
Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
Blood Glucose / metabolism
Carrier Proteins / genetics
Carrier Proteins / metabolism
Cell Line, Tumor
Cell Survival
Diabetes Mellitus, Experimental / enzymology*
Diabetes Mellitus, Experimental / genetics
Diabetes Mellitus, Experimental / pathology
Genotype
Humans
Insulin / blood
Insulin-Secreting Cells / enzymology*
Insulin-Secreting Cells / pathology
Male
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Phenotype
RNA Interference
Signal Transduction
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism*
Thioredoxins / genetics
Thioredoxins / metabolism
Time Factors
Tissue Culture Techniques
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcription, Genetic*
Transfection

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Blood Glucose
Carrier Proteins
Insulin
MLX protein, human
MLXIPL protein, human
Mlxipl protein, mouse
Nuclear Proteins
TXNIP protein, human
Tcfl4 protein, mouse
Transcription Factors
Txnip protein, mouse
Thioredoxins
MTOR protein, human
mTOR protein, mouse
TOR Serine-Threonine Kinases