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.
Despite extensive efforts to understand the monogenic contributions to perturbed glucose homeostasis, the complexity of genetic events that fractionally contribute to the spectrum of this pathology remain poorly understood. Proper maintenance of glucose homeostasis is the central feature of a constellation of comorbidities that define the metabolic syndrome. The ability of the liver to balance carbohydrate uptake and release during the feeding-to-fasting transition is essential to the regulation of peripheral glucose availability. The liver coordinates the expression of gene programs that control glucose absorption, storage, and secretion. Herein, we demonstrate that Steroid Receptor Coactivator 2 (SRC-2) orchestrates a hierarchy of nutritionally responsive transcriptional complexes to precisely modulate plasma glucose availability. Using DNA pull-down technology coupled with mass spectrometry, we have identified SRC-2 as an indispensable integrator of transcriptional complexes that control the rate-limiting steps of hepatic glucose release and accretion. Collectively, these findings position SRC-2 as a major regulator of polygenic inputs to metabolic gene regulation and perhaps identify a previously unappreciated model that helps to explain the clinical spectrum of glucose dysregulation.
Section 1A 48-year-old woman with an alcohol use disorder presented with a subacute onset of altered mental status. Two months prior to presentation, the patient recreationally used morphine, oxycodone, and heroin over the span of 1 week. At the end of this 7-day period, she experienced an episode of lethargy for approximately 24 hours and continued to be difficult to arouse during the following 2 days; however, she did not seek medical attention. She returned to her baseline functional status and remained asymptomatic until 3 weeks later, when she fell and hit her head, initially resulting in a headache. One day later, she began exhibiting bizarre behavior that gradually increased in severity over the following month. She began by sleeping with a recently deceased relative's ashes and emotional labiality and progressed to brushing her teeth with a comb, showering while dressed, undressing and then going outside, and not recognizing family members. Her husband brought her to the hospital for further evaluation.Her neurologic examination demonstrated that she was only oriented to self and had poor comprehension due to an inability to follow commands or respond appropriately to questions. Moreover, she demonstrated apraxia, aphasia, and selective mutism. Additional neurologic findings included patellar hyperreflexia, a palmomental reflex, and a wide-based gait. The remainder of the examination was limited by patient participation.
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