# The Role of ChREBP in Fructose Induced Metabolic Disease

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $451,818

## Abstract

The metabolic syndrome is a cluster of disorders that includes obesity, hypertriglyceridemia,
hypertension, non-alcoholic fatty liver disease and insulin resistance which predispose to the development of
diabetes and cardiovascular disease. Excessive sugar consumption, predominantly in the form of sugar-
sweetened beverages, can contribute to the development of the metabolic syndrome. The mechanisms by which
excessive fructose consumption contributes to metabolic disease remain uncertain. Carbohydrate Responsive-
Element Binding Protein (ChREBP) is a transcription factor which is activated by products of carbohydrate
metabolism and regulates metabolic gene programs and systemic glucose and lipid homeostasis. SNPs in the
ChREBP locus identified in genome-wide association studies predict features of the metabolic syndrome in
human populations. Hepatic and intestinal ChREBP are highly responsive to fructose ingestion. Loss of intestinal
ChREBP results in fructose-intolerance due to fructose malabsorption. In contrast, loss of hepatic ChREBP is
well-tolerated and protects against fructose-induced metabolic disease. Some mouse strains are highly sensitive
to fructose-induced disease whereas others are highly resistant. Preliminary data suggests that this susceptibility
may be mediated by relative differences in intestinal fructose absorption and metabolism, which may affect
delivery of fructose to the liver where it is deleterious. Understanding the molecular determinants of intestinal
versus hepatic fructose metabolism may have important implications for the susceptibility to diet-induced
disease. Through a combination of genetic and dietary models, we will investigate physiological, molecular, and
genetic mechanisms by which ChREBP-mediated intestinal and hepatic fructose metabolism protect against or
contribute to fructose-induced disease. In Aim 1, using an intestine-specific, loss-of-function mouse model, we
will explore the importance of intestinal fructose metabolism in regulating endogenous glucose production and
mediating fructose-induced disease. In Aim 2, we will determine whether the net beneficial versus adverse
effects of hepatic ChREBP activation may be dependent on the metabolic hormone FGF21. In Aim 3, using
fructose sensitive and fructose resistant mice in combination with an intestinal organoid model, we will explore
the molecular mechanisms giving rise to differences in intestinal fructose absorption, metabolism, and
susceptibility to fructose-induced disease. We anticipate that these studies will provide fundamental insight into
mechanisms of fructose-induced metabolic disease and lay the groundwork for novel strategies for the
prevention and treatment of obesity and diabetes.

## Key facts

- **NIH application ID:** 9968965
- **Project number:** 2R01DK100425-07A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** MARK A HERMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $451,818
- **Award type:** 2
- **Project period:** 2014-01-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968965

## Citation

> US National Institutes of Health, RePORTER application 9968965, The Role of ChREBP in Fructose Induced Metabolic Disease (2R01DK100425-07A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9968965. Licensed CC0.

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