Nuclear factor erythroid-2 related factor 2 (Nrf2) plays a pivotal role in cytoprotection against both endogenous and exogenous stresses. Here, we establish a novel molecular link between Nrf2, nuclear receptor SHP (NROB2), lipogenic genes and hepatic lipid homeostasis. Deletion of Nrf2 (Nrf2-/-) in mice resulted in a reduced liver weight, a decrease in fatty acids content of hepatic triacylglycerol, as well as concomitant increases in the levels of serum VLDL-TG, HDL-Cholesterol, and ketone bodies at six months of age. Liver weight and hepatic TG content were consistently lower in Nrf2-/- mice upon a high-fat challenge. This phenotype was accompanied by down-regulation of genes in lipid synthesis and uptake and up-regulation of genes in lipid oxidation in older Nrf2-/- mice. Interestingly, SHP expression was induced with age in Nrf2+/+ mice, but decreased by Nrf2-deficiency. Forced expression and activation of Nrf2 by Nrf2 activators consistently induced SHP expression and Nrf2 was identified as a novel activator of the SHP gene transcription. We also identified PPARγ, Fas, Scd1 and Srebp-1 as direct targets of Nrf2 activation. These findings provide evidence for a role of Nrf2 in the modulation of hepatic lipid homeostasis through transcriptional activation of SHP and lipogenic gene expression.
- nuclear factor erythroid-2 related factor 2
- small heterodimer partner
- lipid metabolism
- Copyright © 2010, American Journal of Physiology- Gastrointestinal and Liver Physiology