Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Intestinal, but not hepatic, ChREBP is required for fructose tolerance
MiSung Kim, … , Guosheng Liang, Mark A. Herman
MiSung Kim, … , Guosheng Liang, Mark A. Herman
Published December 21, 2017
Citation Information: JCI Insight. 2017;2(24):e96703. https://doi.org/10.1172/jci.insight.96703.
View: Text | PDF
Research Article Metabolism

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

  • Text
  • PDF
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.

Authors

MiSung 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

×

Figure 1

Hepatic deletion of ChREBP leads to blunted effects of fructose feeding on body weight and hepatic gene expression.

Options: View larger image (or click on image) Download as PowerPoint
Hepatic deletion of ChREBP leads to blunted effects of fructose feeding ...
(A) Western blot for carbohydrate responsive element–binding protein (ChREBP) protein in liver and perigonadal (PG) adipose tissue whole-cell lysates of control (CTL) and liver-specific ChREBP-KO (LiChKO) mice. (B) Eight-week-old female control and LiChKO mice were fasted for 6 hours, and then gavaged with water or fructose and sacrificed 100 minutes later and hepatic and intestinal gene expression was measured (n = 4 per group). (C and D) Control and LiChKO male mice were fed chow or high-fructose diet (HFrD) starting at 7 weeks of age (n = 5 per group) and body weight was measured weekly. (D) Body composition (EchoMRI) was measured after 8 weeks. Body weights are presented as mean ± SEM. All other data are presented as box-and-whisker plots where the line in the box indicates the median, the box extends from the 25th to 75th percentiles, and the whiskers indicate the minimal and maximal values. P values were obtained using 2-way ANOVA. *P < 0.05 compared between water and fructose within the same genotype; #P < 0.05 compared between different genotypes within the same treatment group.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts