ChREBP: A glucose-activated transcription factor involved in the development of metabolic syndrome

Katsumi Iizuka, Yukio Horikawa

Research output: Contribution to journalReview articlepeer-review

166 Citations (Scopus)

Abstract

Excess carbohydrate intake leads to fat accumulation and insulin resistance. Glucose and insulin coordinately regulate de novo lipogenesis from glucose in the liver, and insulin activates several transcription factors including SREBP1c and LXR, while those activated by glucose remain unknown. Recently, a carbohydrate response element binding protein (ChREBP), which binds to the carbohydrate response element (ChoRE) in the promoter of rat liver type pyruvate kinase (LPK), has been identified. The target genes of ChREBP are involved in glycolysis, lipogenesis, and gluconeogenesis. Although the regulation of ChREBP remains unknown in detail, the transactivity of ChREBP is partly regulated by a phosphorylation/dephosphorylation mechanism. During fasting, protein kinase A and AMP-activated protein kinase phosphorylate ChREBP and inactivate its transactivity. During feeding, xylulose-5-phosphate in the hexose monophosphate pathway activates protein phosphatase 2A, which dephosphorylates ChREBP and activates its transactivity. ChREBP controls 50% of hepatic lipogenesis by regulating glycolytic and lipogenic gene expression. In ChREBP-/- mice, liver triglyceride content is decreased and liver glycogen content is increased compared to wild-type mice. These results indicate that ChREBP can regulate metabolic gene expression to convert excess carbohydrate into triglyceride rather than glycogen. Furthermore, complete inhibition of ChREBP in ob/ob mice reduces the effects of the metabolic syndrome such as obesity, fatty liver, and glucose intolerance. Thus, further clarification of the physiological role of ChREBP may be useful in developing treatments for the metabolic syndrome.

Original languageEnglish
Pages (from-to)617-624
Number of pages8
Journalendocrine journal
Volume55
Issue number4
DOIs
Publication statusPublished - 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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