Intestinal, but not hepatic, ChREBP is required for fructose tolerance

Mi Sung Kim, Inna I. Astapova, Sarah N. Flier, Sarah A. Hannou, Ludivine Doridot, Ashot Sargsyan, Henry H. Kou, Alan J. Fowler, Guosheng Liang, Mark A. Herman

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Increased sugar consumption is a risk factor for the metabolic syndrome including obesity, hypertriglyceridemia, insulin resistance, diabetes, and nonalcoholic fatty liver disease (NAFLD). Carbohydrate responsive element–binding protein (ChREBP) is a transcription factor that responds to sugar consumption to regulate adaptive metabolic programs. Hepatic ChREBP is particularly responsive to fructose and global ChREBP-KO mice are intolerant to diets containing fructose. It has recently been suggested that ChREBP protects the liver from hepatotoxicity following high-fructose diets (HFrDs). We directly tested this hypothesis using tissue-specific ChREBP deletion. HFrD increased adiposity and impaired glucose homeostasis in control mice, responses that were prevented in liver-specific ChREBP-KO (LiChKO) mice. Moreover, LiChKO mice tolerated chronic HFrD without marked weight loss or hepatotoxicity. In contrast, intestine-specific ChREBP-KO (IChKO) mice rapidly lost weight after transition to HFrD, and this was associated with dilation of the small intestine and cecum, suggestive of malabsorption. These findings were associated with downregulation of the intestinal fructose transporter, Slc2a5, which is essential for fructose tolerance. Altogether, these results establish an essential role for intestinal, but not hepatic, ChREBP in fructose tolerance.

Original languageEnglish (US)
Article numbere96703
JournalJCI Insight
Volume2
Issue number24
DOIs
StatePublished - Dec 21 2017
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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