| First Author | Aharoni-Simon M | Year | 2011 |
| Journal | Lab Invest | Volume | 91 |
| Issue | 7 | Pages | 1018-28 |
| PubMed ID | 21464822 | Mgi Jnum | J:173102 |
| Mgi Id | MGI:5009735 | Doi | 10.1038/labinvest.2011.55 |
| Citation | Aharoni-Simon M, et al. (2011) Fatty liver is associated with impaired activity of PPARgamma-coactivator 1alpha (PGC1alpha) and mitochondrial biogenesis in mice. Lab Invest 91(7):1018-28 |
| abstractText | Accumulating evidence indicates that mitochondria have a key role in non-alcoholic fatty liver disease (NAFLD). C57BL/6J mice were fed a choline-deficient, ethionine-supplemented (CDE) diet. Histological studies demonstrated accumulation of fat vacuoles in up to 90% of hepatocytes in mice fed the CDE diet for 14 days. In addition, a decrease in mitochondrial levels, together with an increase in superoxide radicals' levels were observed, indicating elevation of oxidative stress in hepatocytes. ATP levels were decreased in livers from CDE-fed mice after overnight fasting. This was accompanied by a compensative and significant increase in peroxisome-proliferator-activated receptor-gamma coactivator 1alpha (PGC1alpha) mRNA levels in comparison to control livers. However, there was a reduction in PGC1alpha protein levels in CDE-treated mice. Moreover, the expression of mitochondrial biogenesis genes nuclear respiratory factor 1 (NRF-1), mitochondrial transcription factor A (TFAM), mitochondrial transcription factor B1 (TFB1M) and mitochondrial transcription factor B2 (TFB2M), which are all regulated by PGC1alpha activity, remained unchanged in fasted CDE-treated mice. These results indicate impaired activity of PGC1alpha. The impaired activity was further confirmed by chromatin immunoprecipitation analysis, which demonstrated decreased interaction of PGC1alpha with promoters containing NRF-1 and NRF-2 response elements in mice fed the CDE diet. A decrease in PGC1alpha ability to activate the expression of the gluconeogenic gene phosphoenol-pyruvate carboxykinase was also observed. This study demonstrates, for the first time, that attenuated mitochondrial biogenesis in steatotic livers is associated with impaired biological activity of PGC1alpha. |
