ChREBP regulates fructose-induced glucose production independently of insulin signaling
Mi-Sung Kim, … , Michelle Lai, Mark A. Herman
Mi-Sung Kim, … , Michelle Lai, Mark A. Herman
Published September 26, 2016
Citation Information: J Clin Invest. 2016;126(11):4372-4386. https://doi.org/10.1172/JCI81993.
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Research Article Endocrinology Metabolism

ChREBP regulates fructose-induced glucose production independently of insulin signaling

Abstract

Obese, insulin-resistant states are characterized by a paradoxical pathogenic condition in which the liver appears to be selectively insulin resistant. Specifically, insulin fails to suppress glucose production, yet successfully stimulates de novo lipogenesis. The mechanisms underlying this dysregulation remain controversial. Here, we hypothesized that carbohydrate-responsive element-binding protein (ChREBP), a transcriptional activator of glycolytic and lipogenic genes, plays a central role in this paradox. Administration of fructose increased hepatic hexose-phosphate levels, activated ChREBP, and caused glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis in mice. Activation of ChREBP was required for the increased expression of glycolytic and lipogenic genes as well as glucose-6-phosphatase (G6pc) that was associated with the effects of fructose administration. We found that fructose-induced G6PC activity is a major determinant of hepatic glucose production and reduces hepatic glucose-6-phosphate levels to complete a homeostatic loop. Moreover, fructose activated ChREBP and induced G6pc in the absence of Foxo1a, indicating that carbohydrate-induced activation of ChREBP and G6PC dominates over the suppressive effects of insulin to enhance glucose production. This ChREBP/G6PC signaling axis is conserved in humans. Together, these findings support a carbohydrate-mediated, ChREBP-driven mechanism that contributes to hepatic insulin resistance.

Authors

Mi-Sung Kim, Sarah A. Krawczyk, Ludivine Doridot, Alan J. Fowler, Jennifer X. Wang, Sunia A. Trauger, Hye-Lim Noh, Hee Joon Kang, John K. Meissen, Matthew Blatnik, Jason K. Kim, Michelle Lai, Mark A. Herman

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Figure 5

ChREBP mediates the conversion of fructose to glucose.

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ChREBP mediates the conversion of fructose to glucose. We measured accum...
We measured accumulation of glucose in the media after treatment with fructose or lactate+pyruvate from mouse primary hepatocytes obtained from (A) WT mice fed chow versus HFrD for 1 week (n = 3 per group) and (B) chow-fed WT versus ChKO mice (n = 4 per group). P values were obtained by 2-way ANOVA. *P < 0.05 compared with lactate+pyruvate within genotype or diet; #P < 0.05 compared with lactate+pyruvate condition within genotype or diet. (C) Serum fructose concentrations were determined by LC-MS at the indicated time points in 5-hour-fasted, 8- to 12-week-old WT and ChKO male mice after gavage with U13C-fructose (4 g/kg body weight). P values were obtained by Student’s t test. *P < 0.05 compared with WT (n = 5 per group). (D) A schematic diagram illustrating our working hypothesis regarding how ChREBP regulates intracellular hexose-phosphate homeostasis. Increased sugar consumption increases hepatic carbohydrate uptake, which activates ChREBP and increases glycolysis, fatty acid synthesis, and glucose production to dispose of hexose-phosphates such as G6P.