Disruption of circadian rhythms by shift work, obesity, binge feeding, and aging has adverse effects on the health and well-being of the affected individuals. Within the last 10 years, there has been a profound increase in our understanding of how specific transcriptional factors, known as clock genes, regulate and coordinate circadian rhythms within the central nervous system as well as peripheral tissues. The suprachiasmatic nuclei (SCN) in the anterior hypothalamus drive many physiological circadian rhythms such as motor activity, core body temperature, and hormone production. The SCN generates these rhythmic signals through a set of interlocking transcriptional and translational feedback loops that involve six main core genes and proteins. These clock genes have been shown to be present and operational in cells within peripheral organs, including the liver, as well. However, their contribution to the control of local circadian rhythms in these organs is not well-defined. Using genetic methods, investigators have shown that the global disruption of the circadian oscillators in the brain and in peripheral tissues of mice adversely affects metabolism, tumor suppression, and drug-induced organ toxicities. For example, a global CLOCK mutant mouse develops an enlarged fatty liver after chronic ingestion of alcohol. However, global clock gene knockouts or transgenic mice can not address whether the peripheral clocks in hepatocytes themselves modulate alcohol-induced injury and fibrosis in these models. Our central hypotheses are that (1) an evaluation of the circadian regulation of hepatic genes involved in alcohol metabolism and injury will enhance our understanding of the hepatotoxic effects of this agent and (2) the loss of the circadian clock in hepatocytes will exacerbate the liver injury and fibrosis caused by alcohol or high fat alone or in combination. In this project, we will use the newly-characterized murine model of a hepatocyte-specific deletion of Bmal 1, an essential clock component. This deletion disrupts some, but not all, circadian rhythms in the hepatocytes, in part because these cells are still responsive to neural or hormonal circadian signals emanating from the SCN or other organs, such as the adrenal gland and digestive tract, or even paracrine signals, from non-parenchymal cells in the liver. We will use this model to investigate whether the intrinsic circadian clock modulates the expression levels of clock genes, genes involved in alcohol metabolism and injury and fibrogenic genes in the ethanol-high fat model of liver injury and fibrosis. This project will lead to a greater understanding of the role played by hepatocyte clock genes in mediating the various hepatic toxicities of alcohol and high fat as well as the hepatic response to chronic injury.
Shift work, obesity, and atypical eating patterns alter circadian rhythms in the liver. These changes alter the susceptibility of this organ to injury by alcohol, organic solvents and other toxic agents. Understanding the molecular mechanisms by which circadian rhythms modulate liver toxicity will improve our understanding of liver diseases and could lead to novel therapies.