The polyol pathway is an evolutionarily conserved system for sensing glucose uptake

Hiroko Sano; Akira Nakamura; Mariko Yamane; Hitoshi Niwa; Takashi Nishimura; Kimi Araki; Kazumasa Takemoto; Kei-Ichiro Ishiguro; Hiroki Aoki; Yuzuru Kato; Masayasu Kojima

doi:10.1371/journal.pbio.3001678

The polyol pathway is an evolutionarily conserved system for sensing glucose uptake

PLoS Biol. 2022 Jun 10;20(6):e3001678. doi: 10.1371/journal.pbio.3001678. eCollection 2022 Jun.

Authors

Hiroko Sano¹, Akira Nakamura², Mariko Yamane³, Hitoshi Niwa³, Takashi Nishimura⁴, Kimi Araki^{5

6}, Kazumasa Takemoto^{5

7}, Kei-Ichiro Ishiguro⁷, Hiroki Aoki⁸, Yuzuru Kato^{9

10}, Masayasu Kojima¹

Affiliations

¹ Department of Molecular Genetics, Institute of Life Science, Kurume University, Kurume, Fukuoka, Japan.
² Department of Germline Development, Institute of Molecular Embryology and Genetics, and Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Kumamoto, Japan.
³ Department of Pluripotent Stem Cell Biology, Institute of Molecular Embryology and Genetics, and Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Kumamoto, Japan.
⁴ Laboratory of Metabolic Regulation and Genetics, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.
⁵ Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Kumamoto, Japan.
⁶ Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto, Kumamoto, Japan.
⁷ Department of Chromosome Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Kumamoto, Japan.
⁸ Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan.
⁹ Mammalian Development Laboratory, Department of Gene Function and Phenomics, National Institute of Genetics, Mishima, Shizuoka, Japan.
¹⁰ Department of Genetics, SOKENDAI, Mishima, Shizuoka, Japan.

Abstract

Cells must adjust the expression levels of metabolic enzymes in response to fluctuating nutrient supply. For glucose, such metabolic remodeling is highly dependent on a master transcription factor ChREBP/MondoA. However, it remains elusive how glucose fluctuations are sensed by ChREBP/MondoA despite the stability of major glycolytic pathways. Here, we show that in both flies and mice, ChREBP/MondoA activation in response to glucose ingestion involves an evolutionarily conserved glucose-metabolizing pathway: the polyol pathway. The polyol pathway converts glucose to fructose via sorbitol. It has been believed that this pathway is almost silent, and its activation in hyperglycemic conditions has deleterious effects on human health. We show that the polyol pathway regulates the glucose-responsive nuclear translocation of Mondo, a Drosophila homologue of ChREBP/MondoA, which directs gene expression for organismal growth and metabolism. Likewise, inhibition of the polyol pathway in mice impairs ChREBP's nuclear localization and reduces glucose tolerance. We propose that the polyol pathway is an evolutionarily conserved sensing system for glucose uptake that allows metabolic remodeling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors* / metabolism
Carbohydrate Metabolism
Drosophila / metabolism
Glucose* / metabolism
Mice
Polymers
Transcription Factors / metabolism

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
MondoA protein, mouse
Polymers
Transcription Factors
polyol
Glucose

Grants and funding

This work was supported by the following grants: Japan Society for the Promotion of Science KAKENHI 17K07419 and 20K06647 (to HS), 16H06276 (AdAMS) (to HS and KA), 17H03686 and 21H02489 (to AN), 19H05743 and 20H03265 (to KI); The Program of the Joint Usage/Research Center for Developmental Medicine, IMEG, Kumamoto University (to HS); The Joint Research Program of the Institute for Molecular and Cellular Regulation, Gunma University (to HS); The Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care (to HS); MEXT-Supported Program for the Inter-University Research Network for High Depth Omics, IMEG, Kumamoto University (to AN, MY, HN, and KI); MEXT-Supported Program for the Strategic Research Foundation at Private Universities (to HS and MK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.