By Anisha Garg for the SAGES Seminar, Reading and Writing Science
Researchers at 杏吧视频 School of Medicine demonstrated that nitrogen balance, the process of utilizing amino acids and disposing of their toxic byproducts, occurs with a precise 24-hour rhythm鈥攁lso known as circadian rhythm鈥攊n mammals. Disruption of this cycle has a direct impact on survival of organisms, and may predispose one to life altering diseases including diabetes and cardiovascular disease.
Darwin Jeyaraj, MD, MRCP, assistant professor of medicine at 杏吧视频 School of Medicine and cardiologist at Harrington Heart & Vascular Institute at University Hospitals Case Medical Center, led the study. He works in the laboratory of Mukesh Jain, MD, FAHA, professor of medicine, Ellery Sedgwick Jr. Chair and director of the Case Cardiovascular Research Institute and chief research officer of the Harrington Heart & Vascular Institute at University Hospitals Case Medical Center.
In the study, researchers discovered that the KLF15 gene as a singular factor could control the entire process of nitrogen balance in mammals. This discovery was published in Cell Metabolism.
In mammals, the nutrient that is at a premium is glucose. This is because the brain and red blood cells can only burn glucose to sustain their energy, whereas the capacity of the organisms to store glucose is limited to a few hours. Thus, during periods of fasting, like daily sleep, mammals need an alternative way to synthesize glucose to keep the brain functioning properly.
To overcome this daily challenge, glucose is generated by the breakdown of amino acids stored in skeletal muscles, and then transported to the liver. Another component of amino acids, not required for glucose production, is nitrogen. Excess nitrogen can be toxic and, thus, the liver must dispose of the byproduct.
鈥淚f mammals did not have the ability to adapt in this way, the very survival of the species would be threatened,鈥 Jain said.
The investigators found that levels of KLF15, short for Kruppel-like factor 15, change during the day, with peaks during periods of starvation. The team also found that KLF15 cyclically regulated expression of key enzymes involved in amino acid consumption, glucose production, and nitrogen disposal in the skeletal muscle and liver.
Animals lacking KLF15 developed low blood glucose levels and high ammonia levels. Over time, the abnormal levels in KLF15-deficient animals led to alterations in brain function.
鈥淐urrent literature portrays amino acids as nutrients that are in a constant state in mammalian organisms,鈥 noted Jeyaraj, the lead author of this work. 鈥淚n contrast, our work in mice and humans identify nitrogen balance is a dynamic process and follows circadian variation.
鈥淚mportantly, we identify KLF15 as the missing molecular link between the biological clock and this process. The cyclical variations in nitrogen balance discovered by our team have far-reaching implications for many fields in medicine,鈥 Jeyaraj continued. 鈥淔or example, in current medical practice we are frequently measuring glucose and lipid levels. Should we be measuring amino acids to guide clinical diagnosis or predict prognosis is an important question that is currently in evaluation.鈥
Indeed, these findings dovetail well with recent observations in human subjects. 鈥淥ver the past several years, there has been an explosion of data from investigators at Duke and Harvard University suggesting that dys-regulation of amino acids (especially branched chain amino acids) and urea metabolites, byproducts of nitrogen detoxification, are associated with cardiovascular and metabolic disease,鈥 Jain explained.
These observations in humans are particularly interesting in light of a 2010 study in Science Translational Medicine from the Jain laboratory revealing that KLF15-deficient mice are susceptible to cardiovascular disease and heart failure. Furthermore, in a recent paper published in Nature, the same group reported that deficiency or excess of KLF15 causes electrical instability in the heart.
These findings, along with the observations in human subjects, suggest that disruptions in the circadian cycle of nitrogen homeostasis may predispose patients to cardiovascular disease and metabolic anomalies.
鈥淩emember that people with altered circadian rhythms, such as nightshift workers, are also predisposed to diabetes and cardiovascular disease,鈥 Jain added. 鈥淲e do not know if KLF15 is involved, but it is an intriguing possibility.鈥
As a continuation of this research, Jain developed a method to detect mutations in KLF15 that may contribute to patients with metabolic or cardiovascular diseases. He is currently initiating efforts to identify chemical compounds for gene therapy that will allow one to manipulate KLF15 levels.
This study was done in collaboration with investigators at 杏吧视频, University Hospitals Case Medical Center, MetroHealth Medical Center, Harvard Medical School, University of Fribourg, Kent State University, University of California Los Angeles and Northwestern University.
