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Inner workings of molecular thermostat point to pathways to fight diabetes, obesity
Date:9/11/2009

intake. Proteins such as Rev-erbα that help maintain a cell's proper metabolism and energy balance point to their role in such metabolic disorders as obesity and diabetes and suggest ways to intervene.

Rev-erbα is a transcription factor, a protein that binds to DNA in front of, or within, genes to alter their expression. Rev-erbα acts as repressor of gene expression, that is, gene expression goes down when it binds to DNA.

Lazar has been studying the protein for nearly 20 years, yet he never really knew how it worked. What he did know was that, as a member of a family of nuclear receptor proteins, Rev-erbα could bind DNA and likely had an intracellular binding partner.

Typical nuclear receptor proteins are like sensors, registering a specific molecular event and responding accordingly, generally by altering gene expression patterns. So, Lazar asked, "What is the purpose of having a system that responds to changes in cellular heme levels?" He hypothesized that the sensor could act to regulate heme itself.

Working with cultured human and mouse cells his team, led by first author, graduate student Nan Wu, monitored heme levels as Rev-erbα abundance changed. What they found confirmed the protein's role in heme regulation: when overexpressed, heme levels dropped; when suppressed, heme levels rose.

"That was consistent with the hypothesis," says Lazar. "The question was, how does heme do this?"

To figure that out, the team looked for Rev-erbα binding sites within the sequences of genes known to control heme biosynthesis and found one in PGC-1α, a transcription factor that stimulates the production of heme. Since Rev-erb activity is controlled by heme itself, the net effect is that, as heme levels rise, PGC-1α gets repressed, and heme synthesis drops off.

The team also demonstrated the physiological consequence of disrupting this pathway. "We reaso
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Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert  

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