Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 299, Issue 6, Pages G1211-G1221Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00322.2010
Keywords
transcription factors; nuclear receptors; hepatic lipid homeostasis
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Funding
- American Liver Foundation/American Association for the Study of Liver Diseases
- National Institutes of Health [DK080440]
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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 small heterodimer partner (SHP; NROB2), lipogenic genes, and hepatic lipid homeostasis. Deletion of Nrf2 (Nrf2(-/-)) in mice resulted in a reduced liver weight, a decrease in fatty acid content of hepatic triacylglycerol, as well as concomitant increases in the levels of serum VLDL-triglyceride (TG), HDL cholesterol, and ketone bodies at 6 mo of age. Liver weight and hepatic TG content were consistently lower in Nrf2(-/-) mice upon a high-fat challenge. This phenotype was accompanied by downregulation of genes in lipid synthesis and uptake and upregulation 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 PPAR-gamma, 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.
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