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Inner workings of molecular thermostat point to pathways to fight diseases such as diabetes and obesity
by David Hutton  |  Email the author

PHILADELPHIA—Researchers at the University of Pennsylvania School of Medicine have discovered a molecular circuit involving heme that helps maintain proper metabolism in the body, providing new insights into metabolic disorders such as obesity and diabetes.  
Heme is best known as the oxygen-carrying component of hemoglobin, the protein that makes blood red, but it also plays a role in chemical detoxification and energy metabolism within the cell. Heme levels are tightly maintained, and with good reason: Too little heme prevents cell growth and division; excessive amounts of heme are toxic.  
The work builds on 2007 findings from the same team, led by Dr. Mitchell Lazar, director of Penn's Institute for Diabetes, Obesity and Metabolism, showing that a protein called rev-erb coordinates the daily cycles of heme.  
The new research, published recently online in Genes & Development, makes it clear that rev-erb, by controlling the production of heme, also plays a key role in maintaining the body's correct metabolism.
According to Lazar, this happens through a molecular pathway that allows the cell to monitor and adjust internal heme levels, creating more when heme levels fall, and slowing it down when levels rise.  
The circuit is a negative feedback loop, with rev-erb as its central component, explains Lazar.
"Rev-erb is a thermostat for heme," he says.  
When heme levels are high, rev-erb is activated, reducing heme, which leads the cell back towards a normal state. On the other hand, when heme levels are low, Rev-erb alpha activity is low, and this permits the cell to make more heme, again leading back toward a normal state. Maintaining this stasis allows energy metabolism to occur, but avoids harm to the cell due to excessive levels of heme.  
According to Lazar, the findings have huge implications for drug discovery and development.  
"Rev-erb alpha, the heme receptor, is a member of the superfamily of nuclear receptors that includes the receptors for a variety of small molecules including hormones, vitamins, and many drugs," Lazar says. "Thus it is very possible that its activity can be modified by a small molecule."  
Understanding the control of heme levels is likely to be relevant to several diseases.   For example, obesity is a condition where fat tissue builds up due to low-energy expenditure relative to energy intake. Lazar notes that proteins such as rev-erb 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-erb is a transcription factor, a protein that binds to DNA in front of, or within, genes to alter their expression. Rev-erb  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-erb  could bind DNA and likely had an intracellular binding partner.
"We spent many years understanding its molecular properties, but didn't have a clue as to its physiology until Ulli Schibler in Geneva discovered that Rev-erb plays a role in the circadian clock," he says. "That was key to moving ahead with our work, but we still did not know if rev-erb had a ligand that regulated its activity. Our discovery that heme is this key ligand regulator in 2007, simultaneously with another group, was key to moving this forward."
Lazar points out that understanding the control of heme levels is key in the process.   "Heme is a critical part of many intracellular enzymes, including key components in the electron transport chain," he says. "Rev-erb sensing of heme levels seems to help to keep heme levels constant, and this in turn regulates the availability of heme for these critical biochemical processes." 
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-erb 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-erb  binding sites within the sequences of genes known to control heme biosynthesis and found one in PGC-1 alpha, 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-1 alpha gets repressed, and heme synthesis drops off.  
The team also demonstrated the physiological consequence of disrupting this pathway.  
"We reasoned, if heme levels get too low, cells won't like it," Lazar says.
Lazar points out that until now, no one knew there even was a mechanism for keeping heme levels in this narrow range.  
"We've shown that it exists and have defined molecular players that make it work," he says.  
In so doing, he and his team have linked heme biosynthesis with both energy metabolism and the body's internal clock. Rev-erb is a negative regulator of genes involved in energy metabolism. It also, along with PGC-1 and heme, rises and falls over a 24-hour period and even regulates some of the cogs within the clock itself.
The next step, Lazar says, is to determine whether the pathway can be exploited in the clinic.
"We will determine whether rev-erb regulates genes in a circadian manner in a manner that is regulated by heme, and how this integrates metabolism with circadian rhythm," he says.  
Lazar's team team showed that downregulating heme stifled cell division and metabolism, while upregulating heme enhanced them. It therefore is possible, he says, that by pharmacologically "tickling" rev-erb or its other cellular partners to believe the cell has more or less heme than it actually does, researchers may be able to either boost or suppress metabolism accordingly, opening the door to potential therapies for cancer and obesity.  
The research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Lei Yin, Elyisha A. Hanniman and Shree Joshi, all from Penn, are co-authors.
"There's still a lot more to be discovered about rev-erb's biological functions," concludes Lazar. "Continued success will entail finding the target genes and the physiological pathways regulated by rev-erb, and then determining how heme levels both regulate these processes and are themselves regulated."



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