Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/177273
Title: | Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver |
Author: | Satapati, Santhosh Sunny, Nishanth E. Kucejova, Blanka Fu, Xiaorong He, Tian Teng Méndez-Lucas, Andrés Shelton, John M. Perales Losa, Carlos Browning, Jeffrey D. Burgess, Shawn C. |
Keywords: | Àcid cítric Dieta Àcids grassos Fetge Resistència a la insulina Citric acid Diet Fatty acids Liver Insulin resistance |
Issue Date: | 1-Jun-2012 |
Publisher: | American Society for Biochemistry and Molecular Biology |
Abstract: | The manner in which insulin resistance impinges on hepatic mitochondrial function is complex. Although liver insulin resistance is associated with respiratory dysfunction, the effect on fat oxidation remains controversial, and biosynthetic pathways that traverse mitochondria are actually increased. The tricarboxylic acid (TCA) cycle is the site of terminal fat oxidation, chief source of electrons for respiration, and a metabolic progenitor of gluconeogenesis. Therefore, we tested whether insulin resistance promotes hepatic TCA cycle flux in mice progressing to insulin resistance and fatty liver on a high-fat diet (HFD) for 32 weeks using standard biomolecular and in vivo (2)H/(13)C tracer methods. Relative mitochondrial content increased, but respiratory efficiency declined by 32 weeks of HFD. Fasting ketogenesis became unresponsive to feeding or insulin clamp, indicating blunted but constitutively active mitochondrial β-oxidation. Impaired insulin signaling was marked by elevated in vivo gluconeogenesis and anaplerotic and oxidative TCA cycle flux. The induction of TCA cycle function corresponded to the development of mitochondrial respiratory dysfunction, hepatic oxidative stress, and inflammation. Thus, the hepatic TCA cycle appears to enable mitochondrial dysfunction during insulin resistance by increasing electron deposition into an inefficient respiratory chain prone to reactive oxygen species production and by providing mitochondria-derived substrate for elevated gluconeogenesis. |
Note: | Reproducció del document publicat a: https://doi.org/10.1194/jlr.M023382 |
It is part of: | Journal of Lipid Research, 2012, vol. 53, num. 6, p. 1080-1092 |
URI: | http://hdl.handle.net/2445/177273 |
Related resource: | https://doi.org/10.1194/jlr.M023382 |
ISSN: | 0022-2275 |
Appears in Collections: | Articles publicats en revistes (Ciències Fisiològiques) |
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