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Abstract
Mi-Sung Kim,1 Sarah A. Krawczyk,1 Ludivine Doridot,1 Alan J. Fowler,1 Jennifer X. Wang,2 Sunia A. Trauger,2 Hye-Lim Noh,3 Hee Joon Kang,3 John K. Meissen,4 Matthew Blatnik,4 Jason K. Kim,3 Michelle Lai,5 and Mark A. Herman1,6
1Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 2Faculty of Arts and Sciences, Harvard University, Cambridge, Massachusetts, USA. 3Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA. 4Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton, Connecticut, USA. 5Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 6Broad Institute, Cambridge, Massachusetts, USA.
Authorship note: M.S. Kim and S.A. Krawczyk contributed equally to this work.
Address correspondence to: Mark A. Herman, Division of Endocrinology and Metabolism, Duke University Medical Center, 300 North Duke Street, Durham, North Carolina 27701, USA
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.
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