Genetic and Environmental Models of Circadian Disruption Link SRC-2 Function to Hepatic Pathology

Jul 20, 2016Journal of biological rhythms

How Gene and Environmental Disruptions of Body Clocks Are Linked to Liver Disease Through SRC-2 Function

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Abstract

Chronic circadian disruption (CCD) and loss of Steroid Receptor Coactivator-2 (SRC-2) in mice are associated with metabolic syndrome and advanced aging.

Disruption of daily cycles may lead to severe physiological consequences, including metabolic syndrome and advanced aging.
Chronic circadian disruption and SRC-2 ablation in mice resulted in common features of non-alcoholic fatty liver disease (NAFLD).
The combination of SRC-2 loss and CCD produced a phenotype resembling human non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC).
Both CCD and loss of SRC-2 are linked to increased mortality, consistent with findings from other circadian mutant mouse models.
SRC-2 is implicated as a crucial link between light cues and metabolic regulation in the liver.

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Circadian rhythmicity is a fundamental process that synchronizes behavioral cues with metabolic homeostasis. Disruption of daily cycles due to jet lag or shift work results in severe physiological consequences including advanced aging, metabolic syndrome, and even cancer. Our understanding of the molecular clock, which is regulated by intricate positive feedforward and negative feedback loops, has expanded to include an important metabolic transcriptional coregulator, Steroid Receptor Coactivator-2 (SRC-2), that regulates both the central clock of the suprachiasmatic nucleus (SCN) and peripheral clocks including the liver. We hypothesized that an environmental uncoupling of the light-dark phases, termed chronic circadian disruption (CCD), would lead to pathology similar to the genetic circadian disruption observed with loss of SRC-2 We found that CCD and ablation of SRC-2 in mice led to a common comorbidity of metabolic syndrome also found in humans with circadian disruption, non-alcoholic fatty liver disease (NAFLD). The combination of SRC-2(-/-) and CCD results in a more robust phenotype that correlates with human non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) gene signatures. Either CCD or SRC-2 ablation produces an advanced aging phenotype leading to increased mortality consistent with other circadian mutant mouse models. Collectively, our studies demonstrate that SRC-2 provides an essential link between the behavioral activities influenced by light cues and the metabolic homeostasis maintained by the liver.

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Genetic and Environmental Models of Circadian Disruption Link SRC-2 Function to Hepatic Pathology

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