ChREBP Regulates Fructose-induced Glucose Production Independently of Insulin Signaling
Authors
Kim, Mi-SungKrawczyk, Sarah A.
Doridot, Ludivine
Fowler, Alan J.
Wang, Jennifer X.
Trauger, Sunia A.
Noh, Hye Lim
Kang, Hee Joon
Meissen, John K.
Blatnik, Matthew
Kim, Jason K.
Lai, Michelle
Herman, Mark A.
Document Type
Journal ArticlePublication Date
2016-11-01
Metadata
Show full item recordAbstract
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.Source
J Clin Invest. 2016 Nov 1;126(11):4372-4386. doi: 10.1172/JCI81993. Epub 2016 Sep 26. Link to article on publisher's site.DOI
10.1172/JCI81993Permanent Link to this Item
http://hdl.handle.net/20.500.14038/28806PubMed ID
27669460Related Resources
Link to Article in PubMedRights
Publisher PDF posted as allowed by the publisher's author rights policy at http://content-assets.jci.org/admin/forms/jcicopyright.pdf.ae974a485f413a2113503eed53cd6c53
10.1172/JCI81993