Over the past several months, I have proposed that certain environmental illnesses such as chemical sensitivity may be due to alterations in metabolic homeostasis from inflammatory processes and may include dysfunction of the antioxidant system Nrf2 and levels of PGC-1a, possibly through alterations in methylation or some other condition. Several recent studies provides a clearer picture of how this may occur in different tissues. PGC-1a is an important protein that participates in a number of processes including glucose and lipid regulation. (Kelly) In other blogs, we have explained how altered levels are apparent in the tissues of diabetes and for this reason, changes occur in metabolic function. As for Nrf2, it mitigates the effect of inflammatory cytokines as well as, upregulates proteins used in downstream processes of PGC-1a.
For several years now, it has been known that PGC-1a plays an important role in mitochondrial biogenesis and regulates cellular energy metabolism in the liver and muscle and is activated by SIRT1. SIRT1 is another protein we have discussed at length and is activated by the compound resveratrol in red wine and grape skins. Last year, one study showed that in neurons overexpression of SIRT1 or suppression of a GCN5 aminotransferase activated PGC-1a and increased mitochondrial density. Because, several experts have postulated that environmental illnesses may be due to mitochondrial dysfunction from exposures and endogenous processes, increasing mitochondrial density may reduce cellular impairment and increase neuronal survival and provide a therapeutic target.
It seems that GCN5 has the capacity to interact with the PGC family in general. Kelly et al recently found that GCN5 interacts with PGC-1b to repress its transcription activites associated with the estrogen receptor and NRF-1. As a result, the induction of GLUT4 and MCAD were reduced in skeletal muscle which translates to a blunted response of insulin-mediated glucose transport and increases the likelihood of the role of both PGC-1a and PGC-1b in metabolic disease.
As far as Nrf2 goes, in the liver the enzyme ATP citrate lyase (ACL)"relates energy balance" to GCN5 through the control of acetyl-CoA. In a new study by Kitteringham, the findings provide evidence that Nrf2 negatively regulates ATP citrate and therefore may provide a more influential role in glucose and lipid regulation than previously thought. (Kitteringham)
Notes:
***NO derived from constitutive nNOS plays a crucial role in the activity pattern of mitochondrial enzymes. In particular, the NO-mediated suppression of citrate synthase activity may be attributed to a regulatory function of NO in fatty acid synthesis. Inhibition of mitochondrial respiration by NO appears to be at least partially compensated for by a respective increase in the activity of respiratory chain complexes. (Schild) One could suggest the actions of Nrf2 may assist in the regulation of this function.
Kitteringham, N. R., Abdullah, A., Walsh, J., Randle, L., Jenkins, R. E., Sison, R., Goldring, C. E., Powell, H., Sanderson, C., Williams, S., Higgins, L., Yamamoto, M., Hayes, J., and Park, B. K. (2010). Proteomic analysis of nrf2 deficient transgenic mice reveals cellular defence and lipid metabolism as primary nrf2-dependent pathways in the liver. Journal of proteomics, 73(8):1612-1631.
http://www.citeulike.org/user/HEIRS/article/7329576
Jeninga, E. H., Schoonjans, K., and Auwerx, J. (2010). Reversible acetylation of pgc-1: connecting energy sensors and effectors to guarantee metabolic flexibility. Oncogene, aop(current).
http://www.citeulike.org/user/HEIRS/article/7282171
Wareski, P., Vaarmann, A., Choubey, V., Safiulina, D., Liiv, J., Kuum, M., and Kaasik, A. (2009). Pgc-1alpha and pgc-1beta regulate mitochondrial density in neurons. The Journal of biological chemistry, 284(32):21379-21385.
http://www.citeulike.org/user/HEIRS/article/4965303?show_msg=already_posted
Kelly, T. J., Lerin, C., Haas, W., Gygi, S. P., and Puigserver, P. (2009). Gcn5-mediated transcriptional control of the metabolic coactivator pgc-1beta through lysine acetylation. The Journal of biological chemistry, 284(30):19945-19952.
http://www.citeulike.org/user/HEIRS/article/5199678?show_msg=already_posted
Schild, L., Jaroscakova, I., Lendeckel, U., Wolf, G., and Keilhoff, G. (2006). Neuronal nitric oxide synthase controls enzyme activity pattern of mitochondria and lipid metabolism. FASEB J., 20(1):145-147.
http://www.citeulike.org/user/HEIRS/article/7329782
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