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Title: Genetic and environmental models of circadian disruption link SRC-2 function to hepatic pathology

Author
item FLEET, TIFFANY - Baylor College Of Medicine
item STASHI, ERIN - Baylor College Of Medicine
item ZHU, BOKAI - Baylor College Of Medicine
item RAJAPAKSHE, KIMAL - Baylor College Of Medicine
item MARCELO, KATHRINA - Baylor College Of Medicine
item KETTNER, NICOLE - Baylor College Of Medicine
item GORMAN, BLYTHE - Cornell University
item COARFA, CRISTIAN - Baylor College Of Medicine
item FU, LONING - Children'S Nutrition Research Center (CNRC)
item O'MALLEY, BERT - Baylor College Of Medicine
item YORK, BRIAN - Baylor College Of Medicine

Submitted to: Journal of Biological Rhythms
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/17/2016
Publication Date: 10/1/2016
Citation: Fleet, T., Stashi, E., Zhu, B., Rajapakshe, K., Marcelo, K.L., Kettner, N.M., Gorman, B.K., Coarfa, C., Fu, L., O'Malley, B.W., York, B. 2016. Genetic and environmental models of circadian disruption link SRC-2 function to hepatic pathology. Journal of Biological Rhythms. 31(5):443-460.

Interpretive Summary: Circadian rhythm controls metabolic homeostasis in our body. Loss of balance of metabolic homeostasis leads to diseases and also premature aging. Disruption of daily active and sleep cycles have reached epidemic levels in our society. Especially circadian disruption due to jet lag or shift work results in severe physiological consequences including advanced aging, metabolic syndrome, and even cancer. This study investigates the role of the steroid Receptor Coactivator-2 (SRC-2) in regulating circadian rhythm in the liver. We found that the genetic loss of SRC-2 would lead to pathology similar to chronic circadian disruption in humans, including a common comorbidity of metabolic syndrome, fatty liver disease, and advanced aging. Together, these lead to shortening of life span in mice. Thus, our studies demonstrate that SRC-2 provides an essential link between behavioral activities and metabolic homeostasis. Our studies provide experimental demonstration that loss of SRC-2 gene disrupts circadian rhythmicity to induce metabolic syndrome and aging. These findings provide important information to design novel therapeutic strategies for prevention and treatment of metabolic syndrome and premature aging.

Technical Abstract: 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.