How are these two external stimuli integrated to control plasma lipids? Both stimuli require normal Clock activity, as light- and food-entrained regulations are severely curtailed in mice that express a dominant negative mutant Clock (6, 7). At the onset of light, Clock binds to cis-elements in the Small heterodimer partner promoter to increase expression. As concentrations increase, Shp interacts with activators of the MTTP gene to suppress expression. Low MTP activity is associated with reduced plasma lipoproteins. Hence, a transcriptional regulatory mechanism appears to control diurnal changes in plasma lipids (see figure).
The identification that Clock is a predominant regulator of daily rhythms suggests that disruptions in its activity might lead to abnormalities in lipid metabolism. Indeed, mice that express a dominant negative form of Clock show signs of metabolic syndrome (8). Besides normal periodicity of physiological processes, occurrences of several diseases, such as heart attacks, predominantly occur at certain hours of the day. High plasma lipids are risk factors for these diseases. It remains to be determined whether defects in Clock increase susceptibility to cardiovascular diseases such as atherosclerosis.
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M. Mahmood Hussain (Mahmood.Hussain@downstate.edu) is a professor and Xiaoyue Pan (Xiaoyue.Pan@downstate.edu) is a research assistant professor at The State University of New York Downstate Medical Center.