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Differing endoplasmic reticulum stress response to excess lipogenesis versus lipid oversupply in relation to hepatic steatosis and insulin resistance


Mitochondrial dysfunction and endoplasmic reticulum (ER) stress have been implicated in hepatic steatosis and insulin resistance. The present study investigated their roles in the development of hepatic steatosis and insulin resistance during de novo lipogenesis (DNL) compared to extrahepatic lipid oversupply. Male C57BL/6J mice were fed either a high fructose (HFru) or high fat (HFat) diet to induce DNL or lipid oversupply in/to the liver. Both HFru and HFat feeding increased hepatic triglyceride within 3 days (by 3.5 and 2.4 fold) and the steatosis remained persistent from 1 week onwards (p<0.01 vs Con). Glucose intolerance (iAUC increased by approximately 60%) and blunted insulin-stimulated hepatic Akt and GSK3beta phosphorylation ( approximately 40-60%) were found in both feeding conditions (p<0.01 vs Con, assessed after 1 week). No impairment of mitochondrial function was found (oxidation capacity, expression of PGC1alpha, CPT1, respiratory complexes, enzymatic activity of citrate synthase & beta-HAD). As expected, DNL was increased ( approximately 60%) in HFru-fed mice and decreased (32%) in HFat-fed mice (all p<0.05). Interestingly, associated with the upregulated lipogenic enzymes (ACC, FAS and SCD1), two (PERK/eIF2alpha and IRE1/XBP1) of three ER stress pathways were significantly activated in HFru-fed mice. However, no significant ER stress was observed in HFat-fed mice during the development of hepatic steatosis. Our findings indicate that HFru and HFat diets can result in hepatic steatosis and insulin resistance without obvious mitochondrial defects via different lipid metabolic pathways. The fact that ER stress is apparent only with HFru feeding suggests that ER stress is involved in DNL per se rather than resulting from hepatic steatosis or insulin resistance.

Type Journal
ISBN 1932-6203 (Electronic) 1932-6203 (Linking)
Authors Ren, L. P.; Chan, S. M.; Zeng, X. Y.; Laybutt, D. R.; Iseli, T. J.; Sun, R. Q.; Kraegen, E. W.; Cooney, G. J.; Turner, N.; Ye, J. M.;
Publisher Name PLoS One
Published Date 2012-01-01
Published Volume 7
Published Issue 2
Published Pages e30816
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version