Pioglitazone improves hepatic mitochondrial function in a mouse model of nonalcoholic steatohepatitis
| Autor: | Wen-Yi Li, Kenneth Cusi, Joy Guingab, Reginald F. Frye, Srilaxmi Kalavalapalli, Jeremy P. Koelmel, Nishanth E. Sunny, Fernando Bril, Paige Andrews, Richard A. Yost, Timothy J. Garrett, Dhanya Jose, Kaitlyn I Abdo |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Physiology Endocrinology Diabetes and Metabolism Citric Acid Cycle Pyruvate cycling Adipose tissue Mitochondria Liver 030209 endocrinology & metabolism Fructose Oxidative phosphorylation Mitochondrion 03 medical and health sciences 0302 clinical medicine Insulin resistance Non-alcoholic Fatty Liver Disease Physiology (medical) Internal medicine Pyruvic Acid Nonalcoholic fatty liver disease medicine Animals Humans Hypoglycemic Agents Pioglitazone Chemistry Ketones Middle Aged medicine.disease Diet Mice Inbred C57BL Citric acid cycle 030104 developmental biology Endocrinology Adipose Tissue Female Insulin Resistance Amino Acids Branched-Chain Research Article medicine.drug |
| Zdroj: | American Journal of Physiology-Endocrinology and Metabolism. 315:E163-E173 |
| ISSN: | 1522-1555 0193-1849 |
| Popis: | Pioglitazone is effective in improving insulin resistance and liver histology in patients with nonalcoholic steatohepatitis (NASH). Because dysfunctional mitochondrial metabolism is a central feature of NASH, we hypothesized that an important target of pioglitazone would be alleviating mitochondrial oxidative dysfunction. To this end, we studied hepatic mitochondrial metabolism in mice fed high-fructose high-transfat diet (TFD) supplemented with pioglitazone for 20 wk, using nuclear magnetic resonance-based 13C isotopomer analysis. Pioglitazone improved whole body and adipose insulin sensitivity in TFD-fed mice. Furthermore, pioglitazone reduced intrahepatic triglyceride content and fed plasma ketones and hepatic TCA cycle flux, anaplerosis, and pyruvate cycling in mice with NASH. This was associated with a marked reduction in most intrahepatic diacylglycerol classes and, to a lesser extent, some ceramide species (C22:1, C23:0). Considering the cross-talk between mitochondrial function and branched-chain amino acid (BCAA) metabolism, pioglitazone’s impact on plasma BCAA profile was determined in a cohort of human subjects. Pioglitazone improved the plasma BCAA concentration profile in patients with NASH. This appeared to be related to an improvement in BCAA degradation in multiple tissues. These results provide evidence that pioglitazone-induced changes in NASH are related to improvements in hepatic mitochondrial oxidative dysfunction and changes in whole body BCAA metabolism. |
| Databáze: | OpenAIRE |
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