Clock controls plasma lipids
|Both light and food entrainment of plasma lipids requires Clock. Clock/Bmal1 heterodimers interact with the SHP promoter to increase transcription. SHP interacts with activators, such as HNF4α, bound to MTTP promoter and represses their activity, resulting in reduced MTP activity and plasma lipids. In mice expressing a dominant Clock mutant protein, Shp expression and its diurnal regulation is reduced and MTP expression is increased, leading to hyperlipidemia (7).
Light is a dominant external stimulus that entrains several activities of life. The eye transmits information about light to the brain. In the suprachiasmatic nuclei of the brain, this information is processed to increase transcription of the Bmal1 gene. Bmal1 interacts with Clock, and this heterodimer binds to cis-elements in the promoters of Cryptochrome and Period genes and enhances their transcriptions. Cry and Per heterodimers suppress Bmal1 expression. This transcriptional-translational feedback loop recurs every 24 hours and constitutes the biological clock (1 – 3). A critical feature of the biological clock is that it needs constant entrainment by external cues and daily exposure to light to maintain periodicity. Expression of these clock genes is not specific to SCN, but they are expressed in a rhythmic fashion in all the tissues.
The most important activity associated with sunrise is wakefulness. A major activity during wakefulness is eating. Lipids are one of the macronutrients in our food that provide the highest calories per gram. Because of their immiscibility with water, they are assembled into large lipid-protein micelles called lipoproteins. Enterocytes and hepatocytes assemble chylomicrons and very low-density lipoproteins, respectively, to deliver dietary and endogenous fat to other tissues. The assembly of these lipoproteins occurs around a large structural protein called apolipoprotein B, which is aided by an intracellular chaperone, microsomal triglyceride transfer protein.
In humans, plasma lipids are high in the daytime (4), whereas in rodents they are high at night (5). Our studies indicate that mobilization of fat by the liver and intestine is regulated by light and food. Mice kept in constant light or dark fail to show diurnal variations in plasma lipids. By contrast, plasma lipids peak in the daytime if food becomes available at that time. Surprisingly, this food response also is attenuated if mice are kept in constant dark or light. Thus, proper light entrainment is required for temporal reprogramming by food.
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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6. Pan, X. and Hussain, M. M. (2009) J. Lipid Res. 50, 1800 – 1813
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8. Turek, F. W., Joshu, C., Kohsaka, A., Lin, E., Ivanova, G., McDearmon, E., Laposky, A., Losee-Olson, S., Easton, A., Jensen, D. R., Eckel, R. H., Takahashi, J. S., and Bass, J. (2005) Science 308,1043 – 1045
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.