A new study explains how Rev-erbα regulates the time clock in most cells of your body while also regulating metabolic genes in the liver, the site of your body's metabolism of fat and sugar. Interestingly, instead of relying on the same mechanism for both these functions, Rev-erbα performs each of these jobs in distinct ways. This research may provide a new map for scientists wanting to treat metabolic syndrome, a cluster of conditions and symptoms affecting about 25 percent of adults. The signs of this metabolic disease include increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol levels.

Often scientists will discover a component of cellular and bodily processes without understanding how it works. That has been the case with Rev-erbα, a type of protein known as a transcription factor. Aware that Rev-erbα affects both metabolism and the body clock, scientists have been asking one question: Exactly how does it perform each of these separate jobs? By uncoupling the two effects, scientists believe they may be able to work independently with each.

Circadian Rhythms

Rhythms, actually oscillations, guide every physiological process in your body and they begin and end with each individual cell. Each cell in the body contains special proteins that work in a collaborative cascade, creating feedback loops that generate the roughly 24-hour oscillations we commonly call circadian rhythms. A master clock in the brain coordinates and synchronizes all the body clocks, which together influence the patterns of our days by helping to regulate our metabolic, hormonal, and cellular processes.

Each of us, then, is nothing short of an intricately intertwined system of coordinated chemical and physiological responses among cells, organs, systems, and our general environment. One tiny but key component in these processes is Rev-erbα.

For the current study, Dr. Mitchell Lazar, director of the Institute for Diabetes, Obesity, and Metabolism at the Perelman School of Medicine at University of Pennsylvania, and his colleagues explored how this transcription factor regulates a cell’s internal clock and metabolic genes.

What Lazar and his colleagues discovered is Rev-erbα modulates the clock and regulates metabolism by different mechanisms. In its regulation of the clock, Rev-erbα binds directly to the genome and competes with other transcription factors to create a self-sustaining oscillation. In regulation of metabolic genes, Rev-erbα recruits the help of an enzyme, HDAC3, and by doing so exerts a tissue-specific rhythm that regulates metabolism tailored to the specific need of that tissue.

“These two distinct modes of action may give Rev-erbα the ability to stabilize the circadian oscillations of clock genes, while coupling liver metabolism to daily environmental and metabolic changes,” Lazar stated in a press release.

Based on these findings, Lazar believes drugs targeting Rev-erbα’s interaction with the HDAC enzyme or metabolites could modulate liver metabolism without affecting (or only minimally influencing) the overall integrity of the circadian clock. This research could be a step toward treating metabolic disease, especially fatty liver.

Source: Zhang Y, Fang B, Emmett MJ, et al. Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock. Science Express. 2015.