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?±, 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?± 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, "and they don't: They stop growing, and they reduce their oxygen consumption in a manner consistent with the role of heme being used to make ATP," a form of cellular energy.

Lazar states that, "Up 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."

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.

Now the question is, can this pathway be exploited in the clinic. Lazar's team showed that downregulating heme stifled cell division and metabolism, while upregulating heme enhanced them. It therefore is possible, Lazar 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.

Source: University of Pennsylvania School of Medicine