Regulation of hepatic mitochondrial biogenesis and function

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As reported recently, AMPK has been also involved in the control of mitochondrial biogenesis in the liver, a role already evidenced in skeletal muscles (Reznick and Shulman, 2006). First evidences were brought by treatment with resveratrol, a polyphenol constituent of red wine, which increases mitochondrial number in liver in association with AMPK activation (Baur et al., 2006). Second, AMPKa1a2_LS-/- mice have reduced mitochondrial biogenesis as suggested by decreased transcript and protein expression of key mitochondrial constituents such as peroxisome proliferator-activated receptor-g coactivator-1 a (PGC-1a), cytochrome c oxidase I (COX I), COX IV and cytochrome c genes (Guigas et al., 2007) (Figure 1). Interestingly, both mitochondrial respiration and basal level of ATP were also significantly lower in hepatocytes isolated from AMPKa1a2_LS-/- mice compared with control mice (Guigas et al., 2006). This result emphasizes the importance of AMPK in the regulation of cellular energy homeostasis via the control of adaptive mitochondrial function. Thus, diminished AMPK activity may be an important contributing factor in the reduced mitochondrial function and dysregulated intracellular lipid metabolism associated with hepatic insulin resistance. The exact mechanisms by which deletion of AMPK in the liver affects PGC-1a expression and mitochondrial biogenesis remain to be elucidated but could be due to a lack of protein-protein interaction, as suggested in skeletal muscle (Jager et al., 2007).