Free Fatty Acids and Cytokines Induce Pancreatic β-Cell Apoptosis by Different Mechanisms: Role of Nuclear Factor-κB and Endoplasmic Reticulum Stress
Open Access
- 1 November 2004
- journal article
- Published by The Endocrine Society in Endocrinology
- Vol. 145 (11), 5087-5096
- https://doi.org/10.1210/en.2004-0478
Abstract
Apoptosis is probably the main form of β-cell death in both type 1 diabetes mellitus (T1DM) and T2DM. In T1DM, cytokines contribute to β-cell destruction through nuclear factor-κB (NF-κB) activation. Previous studies suggested that in T2DM high glucose and free fatty acids (FFAs) are β-cell toxic also via NF-κB activation. The aims of this study were to clarify whether common mechanisms are involved in FFA- and cytokine-induced β-cell apoptosis and determine whether TNFα, an adipocyte-derived cytokine, potentiates FFA toxicity through enhanced NF-κB activation. Apoptosis was induced in insulinoma (INS)-1E cells, rat islets, and fluorescence-activated cell sorting-purified β-cells by oleate, palmitate, and/or cytokines (IL-1β, interferon-γ, TNFα). Palmitate and IL-1β induced a similar percentage of apoptosis in INS-1E cells, whereas oleate was less toxic. TNFα did not potentiate FFA toxicity in primary β-cells. The NF-κB-dependent genes inducible nitric oxide synthase and monocyte chemoattractant protein-1 were induced by IL-1β but not by FFAs. Cytokines activated NF-κB in INS-1E and β-cells, but FFAs did not. Moreover, FFAs did not enhance NF-κB activation by TNFα. Palmitate and oleate induced C/EBP homologous protein, activating transcription factor-4, and immunoglobulin heavy chain binding protein mRNAs, X-box binding protein-1 alternative splicing, and activation of the activating transcription factor-6 promoter in INS-1E cells, suggesting that FFAs trigger an endoplasmic reticulum (ER) stress response. We conclude that apoptosis is the main mode of FFA- and cytokine-induced β-cell death but the mechanisms involved are different. Whereas cytokines induce NF-κB activation and ER stress (secondary to nitric oxide formation), FFAs activate an ER stress response via an NF-κB- and nitric oxide-independent mechanism. Our results argue against a unifying hypothesis for the mechanisms of β-cell death in T1DM and T2DM.Keywords
This publication has 73 references indexed in Scilit:
- Protein Kinase B/Akt Prevents Fatty Acid-induced Apoptosis in Pancreatic β-Cells (INS-1)Published by Elsevier BV ,2002
- Fatty acids potentiate interleukin-1β toxicity in the β-cell line INS-1EBiochemical and Biophysical Research Communications, 2002
- IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNANature, 2002
- XBP1 mRNA Is Induced by ATF6 and Spliced by IRE1 in Response to ER Stress to Produce a Highly Active Transcription FactorCell, 2001
- A Comprehensive Analysis of Cytokine-induced and Nuclear Factor-κB-dependent Genes in Primary Rat Pancreatic β-CellsPublished by Elsevier BV ,2001
- Apoptosis in insulin-secreting cells. Evidence for the role of intracellular Ca2+ stores and arachidonic acid metabolism.JCI Insight, 1998
- Studies on the molecular regulation of the inducible form of nitric oxide synthase (iNOS) in insulin-producing cellsMolecular and Cellular Endocrinology, 1994
- TNF-α and IFN-γ potentiate the deleterious effects of IL-1β on mouse pancreatic islets mainly via generation of nitric oxideCytokine, 1994
- Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle.JCI Insight, 1994
- Dietary Fat Predicts Conversion From Impaired Glucose Tolerance to NIDDM: The San Luis Valley Diabetes StudyDiabetes Care, 1994