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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 Article has an altmetric score of 192

ChREBP regulates fructose-induced glucose production independently of insulin signaling

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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 3

Multiple different carbohydrates acutely activate hepatic ChREBP.

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Multiple different carbohydrates acutely activate hepatic ChREBP.
(A–C) ...
(A–C) Five-hour-fasted, 8-week-old C3H/HeJ male mice were gavaged with water, glucose (4 g/kg body weight), or fructose (4 g/kg body weight) and sacrificed 100 minutes later. (A) Hepatic gene expression was measured by qPCR. P values were obtained by 1-way ANOVA. *P < 0.05 compared with water; **P < 0.05 compared with all others (n = 6 per group). (B) Nuclear and cytosolic ChREBP-α and the ratio of nuclear to cytosolic ChREBP-α from water- versus fructose-gavaged mice were measured by Western blot and quantified (n = 4 per group). P values were obtained by Student’s t test. *P < 0.05 compared with water. (C) ChIP was performed from liver tissue with anti-ChREBP antibody or IgG control and qPCR was performed on immunoprecipitated chromatin with primers spanning the E-box in the ChREBP-β promoter, the carbohydrate response element in the G6pc promoter, and a nonspecific genomic region. P values were obtained by 1-way ANOVA. †P < 0.05 compared with water- and glucose-ChREBP groups (n = 4 per group). (D) Five-hour-fasted, 8-week-old C3H/HeJ male mice were gavaged with glucokinase activator (PF-04991532, 100 mg/kg body weight) and then gavaged with water or glucose (4 g/kg body weight) 30 minutes later. Mice were sacrificed 100 minutes later and hepatic gene expression was measured by qPCR. P values were obtained by 2-way ANOVA. *P < 0.05 compared with methylcellulose (MC) within water- or glucose-gavaged groups; #P < 0.05 compared with water within MC- or GKA-gavaged groups (n = 6 per group). (E) Five-hour-fasted, 8-week-old C3H/HeJ male mice were gavaged with water or glycerol (4 g/kg body weight) and sacrificed 100 minutes later. P values were obtained by Student’s t test. *P < 0.05 compared with water (n = 6 per group). Values are the mean ± SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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