Coordinate Changes in Histone Modifications, mRNA Levels, and Metabolite Profiles in Clonal INS-1 832/13 β-Cells Accompany Functional Adaptations to Lipotoxicity

• Published in: The Journal of biological chemistry Vol. 288; no. 17; pp. 11973 - 11987
• Main Authors: Malmgren, Siri, Spégel, Peter, Danielsson, Anders P.H., Nagorny, Cecilia L., Andersson, Lotta E., Nitert, Marloes Dekker, Ridderstråle, Martin, Mulder, Hindrik, Ling, Charlotte
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.04.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Beta Cell; Cell Line, Tumor; Citric Acid Cycle - drug effects; Clinical Medicine; Endocrinology and Diabetes; Endokrinologi och diabetes; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacology; Epigenesis, Genetic - drug effects; Epigenetics; Histone Modification; Histones - genetics; Histones - metabolism; Humans; Insulin - genetics; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - metabolism; Klinisk medicin; Lipotoxicity; Medical and Health Sciences; Medicin och hälsovetenskap; Metabolic Regulation; Metabolism; Metabolomics; Oxygen Consumption - drug effects; Palmitic Acid - adverse effects; Palmitic Acid - pharmacology; Protein Processing, Post-Translational - drug effects; Rats; RNA, Messenger - genetics; RNA, Messenger - metabolism; Metabolomics; Histone Modification; Beta Cell; Metabolic Regulation; Epigenetics; Lipotoxicity; Insulin Secretion
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M112.422527

Lipotoxicity is a presumed pathogenetic process whereby elevated circulating and stored lipids in type 2 diabetes cause pancreatic β-cell failure. To resolve the underlying molecular mechanisms, we exposed clonal INS-1 832/13 β-cells to palmitate for 48 h. We observed elevated basal insulin secretion but impaired glucose-stimulated insulin secretion in palmitate-exposed cells. Glucose utilization was unchanged, palmitate oxidation was increased, and oxygen consumption was impaired. Halting exposure of the clonal INS-1 832/13 β-cells to palmitate largely recovered all of the lipid-induced functional changes. Metabolite profiling revealed profound but reversible increases in cellular lipids. Glucose-induced increases in tricarboxylic acid cycle intermediates were attenuated by exposure to palmitate. Analysis of gene expression by microarray showed increased expression of 982 genes and decreased expression of 1032 genes after exposure to palmitate. Increases were seen in pathways for steroid biosynthesis, cell cycle, fatty acid metabolism, DNA replication, and biosynthesis of unsaturated fatty acids; decreases occurred in the aminoacyl-tRNA synthesis pathway. The activity of histone-modifying enzymes and histone modifications of differentially expressed genes were reversibly altered upon exposure to palmitate. Thus, Insig1, Lss, Peci, Idi1, Hmgcs1, and Casr were subject to epigenetic regulation. Our analyses demonstrate that coordinate changes in histone modifications, mRNA levels, and metabolite profiles accompanied functional adaptations of clonal β-cells to lipotoxicity. It is highly likely that these changes are pathogenetic, accounting for loss of glucose responsiveness and perturbed insulin secretion. Background: Epigenetic regulation may mediate lipotoxic effects on β-cells in type 2 diabetes. Results: Lipotoxicity impairs insulin secretion, and alters metabolism, gene expression, and histone marks in INS-1 832/13 β-cells. Conclusion: Perturbed insulin secretion results from epigenetic, genetic, and metabolic adaptations to increased fatty acid metabolism in β-cells. Significance: Elucidation of the link between lipotoxicity and insulin secretion is crucial for understanding the pathogenesis of type 2 diabetes.