TY - JOUR
T1 - Genetic and Environmental Models of Circadian Disruption Link SRC-2 Function to Hepatic Pathology
AU - Fleet, Tiffany
AU - Stashi, Erin
AU - Zhu, Bokai
AU - Rajapakshe, Kimal
AU - Marcelo, Kathrina L.
AU - Kettner, Nicole M.
AU - Gorman, Blythe
AU - Coarfa, Cristian
AU - Fu, Loning
AU - O'Malley, Bert W.
AU - York, Brian
N1 - Funding Information:
We thank Rainer Lanz for lessons on relational database management. We thank Sean McGuire for critical reading of the manuscript. We thank Dr. Corey Reynolds from the Mouse Phenotyping Core at BCM for technical support. This research was supported by grants from the NIH (F31DK107254 to T.F., F31CA171350 to E.S., P01 DK59820 and 3U19DK062434-10W1 to B.W.O.) and Diabetes Research Center (DRC) grant NIDDK-P30 DK079638. Partial support was provided by NIH grant GM033976. Additionally, research support was provided by the Welch Foundation (Q1521) and from the Center for the Advancement of Science in Space (CASIS) Integrated OMICs Award to B.Y. and B.W.O. Partial support for this work was provided by a grant to Baylor College of Medicine from the Howard Hughes Medical Institutes through the Med into Grad Initiative, and to the Medical Scientist Training Program NIGMS T32 GM7330.
Publisher Copyright:
© SAGE Publications.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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.
AB - 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.
KW - NAFLD
KW - SRC-2
KW - chronic circadian disruption
KW - liver
KW - metabolism
KW - non-alcoholic fatty liver disease
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U2 - 10.1177/0748730416657921
DO - 10.1177/0748730416657921
M3 - Article
C2 - 27432117
AN - SCOPUS:84988419088
SN - 0748-7304
VL - 31
SP - 443
EP - 460
JO - Journal of Biological Rhythms
JF - Journal of Biological Rhythms
IS - 5
ER -