Interaction of Diet with the Metabolic Flux Signatures of the Unfolded Protein Response

OBJECTIVES: Endoplasmic reticulum (ER) stress is involved in the progression of several diseases, including diet and obesity-related conditions such as nonalcoholic fatty liver disease. Our goal was to understand the role of diet on the unfolded protein response (UPR), an important pathway in ER stress response, in efforts to elucidate the role of the UPR in the progression to non-alcoholic fatty liver disease. METHODS: We used stable isotope labeling with tandem mass spectrometric analysis to characterize proteome-wide synthesis rates and de novo lipogenesis rates in vivo in mouse liver to generate metabolic flux signatures of the unfolded protein response. We initiated the unfolded protein response through treatment with tunicamycin. Diets rich in either unsaturated, oleic, acids, or saturated, palmitic, acids were given to mice for five weeks to determine the effect of dietary fatty acids on this induced ER stress response. RESULTS: With induction of the unfolded protein response, we observed reduced protein synthesis across most ontologies, but increased synthesis of ER proteins and chaperones. We also found reduced de novo lipogenesis after 48 and 72 hours of induced ER stress. Reduction in food intake and significant weight loss also occurred after 48 and 72 hours. Electron microscopy revealed striking morphological differences in the ER and accumulation of lipid droplets with ER stress. Diets high in unsaturated fatty acids had a lesser impact on the progression of the unfolded protein response. CONCLUSIONS: These data begin to characterize how the unfolded protein response progresses over time, and the metabolic changes that occur with ER stress. Diets rich in saturated or unsaturated fatty acids had different effects on the metabolic signatures of the UPR, suggesting the type dietary fatty acid is important in properly handling ER stress. FUNDING SOURCES: NIH.