title: Genetic and Environmental Models of Circadian Disruption Link SRC-2 Function to Hepatic Pathology.
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.
authors.affiliation: Interdepartmental Department in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Fleet
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Erin
authors.initials: E
authors.lastname: Stashi
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Bokai
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Kimal
authors.initials: K
authors.lastname: Rajapakshe
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Kathrina L
authors.initials: KL
authors.lastname: Marcelo
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Kettner
authors.affiliation: Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas Weill Medical College, Cornell University, New York, New York.
authors.forename: Blythe K
authors.initials: BK
authors.lastname: Gorman
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Loning
authors.initials: L
authors.lastname: Fu
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas york@bcm.edu.
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas york@bcm.edu.
authors.forename: Brian
authors.initials: B
authors.lastname: York
mesh_terms: D000375:Aging; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D057906:Circadian Clocks; D002940:Circadian Rhythm / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000235:genetics; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000503:physiopathology; D051958:Nuclear Receptor Coactivator 2 / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D056950:Period Circadian Proteins / Q000235:genetics; D017440:Photoperiod; D013493:Suprachiasmatic Nucleus / Q000502:physiology
chemical_list: D051958:Nuclear Receptor Coactivator 2; D056950:Period Circadian Proteins
keywords: NAFLD; SRC-2; chronic circadian disruption; liver; metabolism; non-alcoholic fatty liver disease