Hepatospecific effects of fructose on c-jun NH2-terminal kinase: implications for hepatic insulin resistance
- 1 November 2004
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Endocrinology and Metabolism
- Vol. 287 (5), E926-E933
- https://doi.org/10.1152/ajpendo.00185.2004
Abstract
Sucrose- and fructose-enriched diets produce hepatic insulin resistance in rats independently of obesity. In humans, fructose infusion results in impaired insulin regulation of glucose production. The aim of the present study was to identify intrahepatic mediators of sucrose- and fructose-induced hepatic insulin resistance. In study 1, male rats were fed a control diet (STD, 68% of energy from corn starch, 12% from corn oil) or a sucrose-enriched diet (HSD, 68% sucrose, 12% corn oil) for 1, 2, or 5 wk. HSD produced hepatic insulin resistance at all time points. Hepatic protein tyrosine phosphatase 1B protein levels and activity were increased at 5 wk only, whereas c-jun NH2-terminal kinase (JNK) activity was increased at all time points. Normalization of JNK activity in hepatocytes isolated from HSD rats improved insulin-stimulated tyrosine phosphorylation of insulin receptor substrate (IRS) proteins and insulin suppression of glucose release. In study 2, male rats were provided STD for 1 wk and then were either fasted or fasted and refed either STD or HSD for 3 or 6 h. Rats refed HSD were characterized by increased hepatic JNK activity and phosphorylation of IRS1 on Ser307 after 6 h only. In study 3, hyperglycemic, hyperinsulinemic pancreatic clamps were performed for 3 or 6 h in the presence or absence of low or high intraportal fructose infusions. High intraportal fructose infusions, which increased portal vein fructose concentration to ∼1 mM, increased hepatic JNK activity and phosphorylation of IRS1 on Ser307 at 6 h only. These data suggest that sucrose- and fructose-induced hepatic insulin resistance are mediated, in part, via activation of JNK activity. Thus high rates of fructose metabolism in the liver appear to acutely activate stress pathways.Keywords
This publication has 39 references indexed in Scilit:
- A central role for JNK in obesity and insulin resistanceNature, 2002
- Hepatic Very Low Density Lipoprotein-ApoB Overproduction Is Associated with Attenuated Hepatic Insulin Signaling and Overexpression of Protein-tyrosine Phosphatase 1B in a Fructose-fed Hamster Model of Insulin ResistanceJournal of Biological Chemistry, 2002
- Acute Fructose Administration Decreases the Glycemic Response to an Oral Glucose Tolerance Test in Normal AdultsJournal of Clinical Endocrinology & Metabolism, 2000
- A High-Sucrose Diet Alters the Lipid Composition and Fluidity of Liver Sinusoidal MembranesHormone and Metabolic Research, 1998
- Transcriptional Glucose Signaling through The Glucose Response Element Is Mediated by the Pentose Phosphate PathwayPublished by Elsevier ,1996
- Purification and Characterization of a Novel Xylulose 5-Phosphate-activated Protein Phosphatase Catalyzing Dephosphorylation of Fructose-6-phosphate,2-kinase:Fructose-2,6-bisphosphatasePublished by Elsevier ,1995
- Genetic and environmental determinants of non‐insulin‐dependent diabetes mellitus (NIDDM)Diabetes/Metabolism Research and Reviews, 1992
- Regulation of Net Hepatic Glucose Uptake In VivoAnnual Review of Physiology, 1992
- Stimulation of glucose phosphorylation by fructose in isolated rat hepatocytesEuropean Journal of Biochemistry, 1989
- HIGH-YIELD PREPARATION OF ISOLATED RAT LIVER PARENCHYMAL CELLSThe Journal of cell biology, 1969