Curcumin ameliorates mitochondrial dysfunction associated with inhibition of gluconeogenesis in free fatty acid-mediated hepatic lipoapoptosis

Kuo,Jong-Jen; Chang,Hen-Hong; Tsai,Tung-Hu; Lee,Tzung-Yan

doi:10.3892/ijmm.2012.1020

Curcumin ameliorates mitochondrial dysfunction associated with inhibition of gluconeogenesis in free fatty acid-mediated hepatic lipoapoptosis

Authors:
- Jong-Jen Kuo
- Hen-Hong Chang
- Tung-Hu Tsai
- Tzung-Yan Lee
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Affiliations: Institute of Traditional Medicine, National Yang Ming University, Taipei, Taiwan, R.O.C., Graduate Institute of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan, R.O.C.
Published online on: June 11, 2012 https://doi.org/10.3892/ijmm.2012.1020
Pages: 643-649

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Abstract

Insulin resistance occurs in almost all patients with non-alcoholic fatty liver disease (NAFLD), and mitochondrial dysfunction likely plays a pivotal role in the progression of fatty liver into non-alcoholic steatohepatitis (NASH). Curcumin is a compound derived from the spice turmeric, a spice that is a potent antioxidant, anti-carcinogenic, and anti-hepatotoxic agent. The aim of this study was to analyze the ability of curcumin to protect against the mitochondrial impairment induced by high free fatty acids (HFFAs) and to determine the underlying mechanism for this cytoprotection. Curcumin treatment inhibited the lipoapoptosis, ROS production and ATP depletion elicited by HFFA in primary hepatocytes. We demonstrate that curcumin effectively suppressed HFFA-induced production of phosphoenol pyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in hepatocytes. Not only did curcumin treatment increase mitochondrial DNA (mtDNA) copy number in hepatocytes, but it also increased levels of transcriptional factors that regulate mitochondrial biogenesis, including peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (Tfam). In addition, curcumin contributed to cell survival, as indicated by the restoration of the mitochondrial membrane potential (MMP) and the inhibition of the mitochondrial biogenesis induced by HFFA. Furthermore, this cytoprotection resulted from curcumin-mediated downregulation of the NF-κB p65 subunit, thereby inhibiting lipoapoptosis. Together, these data suggest that curcumin protects hepatocytes from HFFA-induced lipoapoptosis and mitochondrial dysfunction, which partially occurs through the regulation of mitochondrial biogenesis.

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