These findings were associated with downregulation of the intestinal fructose transporter, Slc2a5, which is essential for fructose tolerance. 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. Moreover, LiChKO mice tolerated chronic HFrD without marked weight loss or hepatotoxicity. HFrD increased adiposity and impaired glucose homeostasis in control mice, responses that were prevented in liver-specific ChREBP-KO (LiChKO) mice. We directly tested this hypothesis using tissue-specific ChREBP deletion. It has recently been suggested that ChREBP protects the liver from hepatotoxicity following high-fructose diets (HFrDs). Hepatic ChREBP is particularly responsive to fructose and global ChREBP-KO mice are intolerant to diets containing fructose. Carbohydrate responsive element–binding protein (ChREBP) is a transcription factor that responds to sugar consumption to regulate adaptive metabolic programs. Increased sugar consumption is a risk factor for the metabolic syndrome including obesity, hypertriglyceridemia, insulin resistance, diabetes, and nonalcoholic fatty liver disease (NAFLD).
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