Dissociation of inositol-requiring enzyme (IRE1α)-mediated c-Jun N-terminal kinase activation from hepatic insulin resistance in conditional X-box-binding protein-1 (XBP1) knock-out mice
| Autor: | Blas A. Guigni, François R Jornayvaz, Hui-Young Lee, Mario Kahn, Laurie H. Glimcher, Ann-Hwee Lee, Andreas L. Birkenfeld, Gerald I. Shulman, Varman T. Samuel, Michael J. Jurczak |
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| Rok vydání: | 2011 |
| Předmět: |
X-Box Binding Protein 1
Protein-Serine-Threonine Kinases/genetics/metabolism Eukaryotic Initiation Factor-2 Transcription Factors/genetics/metabolism Endoplasmic Reticulum Biochemistry JNK Mitogen-Activated Protein Kinases/genetics/metabolism Ceramide Mice 0302 clinical medicine Glucose Metabolism Heat-Shock Proteins/genetics/metabolism Endoribonucleases/genetics/metabolism Phosphorylation Endoplasmic Reticulum Chaperone BiP Heat-Shock Proteins Mice Knockout 0303 health sciences Liver Metabolism Eukaryotic Initiation Factor-2/genetics/metabolism Endoplasmic Reticulum Stress 3. Good health DNA-Binding Proteins Liver 030220 oncology & carcinogenesis ER Stress Diacylglycerol Signal Transduction Liver/metabolism medicine.medical_specialty XBP1 Insulin Receptor Substrate Proteins Knockout Regulatory Factor X Transcription Factors Biology Protein Serine-Threonine Kinases 03 medical and health sciences Insulin resistance Internal medicine Protein Kinase C (PKC) Endoribonucleases medicine Animals Molecular Biology 030304 developmental biology Diacylglycerol kinase Endoplasmic reticulum JNK Mitogen-Activated Protein Kinases Gluconeogenesis Lipid metabolism Insulin Receptor Substrate Proteins/genetics/metabolism Cell Biology medicine.disease Lipid Metabolism IRS2 Endocrinology Metabolism DNA-Binding Proteins/genetics/metabolism Unfolded protein response Signal Transduction/genetics Endoplasmic Reticulum/genetics/metabolism Insulin Resistance Transcription Factors |
| Zdroj: | The Journal of Biological Chemistry Journal of Biological Chemistry, Vol. 287, No 4 (2012) pp. 2558-67 |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | Background: Endoplasmic reticulum (ER) stress has been implicated in causing hepatic insulin resistance. Results: Fructose-fed XBP1 knock-out mice were protected from hepatic insulin resistance despite increased hepatic ER stress and JNK activation. Conclusion: ER stress and hepatic JNK activation can be disassociated from hepatic insulin resistance. Significance: Hepatic ER stress is not a direct causal factor in hepatic insulin resistance. Hepatic insulin resistance has been attributed to both increased endoplasmic reticulum (ER) stress and accumulation of intracellular lipids, specifically diacylglycerol (DAG). The ER stress response protein, X-box-binding protein-1 (XBP1), was recently shown to regulate hepatic lipogenesis, suggesting that hepatic insulin resistance in models of ER stress may result from defective lipid storage, as opposed to ER-specific stress signals. Studies were designed to dissociate liver lipid accumulation and activation of ER stress signaling pathways, which would allow us to delineate the individual contributions of ER stress and hepatic lipid content to the pathogenesis of hepatic insulin resistance. Conditional XBP1 knock-out (XBP1Δ) and control mice were fed fructose chow for 1 week. Determinants of whole-body energy balance, weight, and composition were determined. Hepatic lipids including triglyceride, DAGs, and ceramide were measured, alongside markers of ER stress. Whole-body and tissue-specific insulin sensitivity were determined by hyperinsulinemic-euglycemic clamp studies. Hepatic ER stress signaling was increased in fructose chow-fed XBP1Δ mice as reflected by increased phosphorylated eIF2α, HSPA5 mRNA, and a 2-fold increase in hepatic JNK activity. Despite JNK activation, XBP1Δ displayed increased hepatic insulin sensitivity during hyperinsulinemic-euglycemic clamp studies, which was associated with increased insulin-stimulated IRS2 tyrosine phosphorylation, reduced hepatic DAG content, and reduced PKCϵ activity. These studies demonstrate that ER stress and IRE1α-mediated JNK activation can be disassociated from hepatic insulin resistance and support the hypothesis that hepatic insulin resistance in models of ER stress may be secondary to ER stress modulation of hepatic lipogenesis. |
| Databáze: | OpenAIRE |
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