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

Fleet, Tiffany; Stashi, Erin; Zhu, Bokai; Rajapakshe, Kimal; Marcelo, Kathrina; Kettner, Nicole M.; Gorman, Blythe; Coarfa, Cristian; Fu, Loning; O’Malley, Bert W.; York, Brian

doi:10.1177/0748730416657921

Cited by 23 publications

(16 citation statements)

References 56 publications

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“…Kettner et al demonstrated that chronic circadian disruption induces NAFLD and spontaneous hepatocarcinogenesis, promotes genome-wide deregulation and metabolic disruption, and activates CAR (NR1I3, constitutive androstane receptor) which drives NAFLD to NASH, fibrosis and HCC progression (78). Chronic circadian disruption in mice had a profound effect on metabolism, what was also observed in humans and circadian disruption with or without steroid receptor Coactivator-2 (SRC-2) ablation showed association with human HCC gene signature (79). The TIMELESS protein has oncogenic function in human HCC as well (80).…”

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 83%

Oxysterols and Gastrointestinal Cancers Around the Clock

et al. 2019

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This review focuses on the role of oxidized sterols in three major gastrointestinal cancers (hepatocellular carcinoma, pancreatic, and colon cancer) and how the circadian clock affects the carcinogenesis by regulating the lipid metabolism and beyond. While each field of research (cancer, oxysterols, and circadian clock) is well-studied within their specialty, little is known about the intertwining mechanisms and how these influence the disease etiology in each cancer type. Oxysterols are involved in pathology of these cancers, but final conclusions about their protective or damaging effects are elusive, since the effect depends on the type of oxysterol, concentration, and the cell type. Oxysterol concentrations, the expression of key regulators liver X receptors (LXR), farnesoid X receptor (FXR), and oxysterol-binding proteins (OSBP) family are modulated in tumors and plasma of cancer patients, exposing these proteins and selected oxysterols as new potential biomarkers and drug targets. Evidence about how cholesterol/oxysterol pathways are intertwined with circadian clock is building. Identified key contact points are different forms of retinoic acid receptor related orphan receptors (ROR) and LXRs. RORs and LXRs are both regulated by sterols/oxysterols and the circadian clock and in return also regulate the same pathways, representing a complex interplay between sterol metabolism and the clock. With this in mind, in addition to classical therapies to modulate cholesterol in gastrointestinal cancers, such as the statin therapy, the time is ripe also for therapies where time and duration of the drug application is taken as an important factor for successful therapies. The final goal is the personalized approach with chronotherapy for disease management and treatment in order to increase the positive drug effects.

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Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 83%

Oxysterols and Gastrointestinal Cancers Around the Clock

et al. 2019

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“…It has been demonstrated that disruption of the circadian system can have significant implications for liver metabolism and the formation of NAFLD. For instance, knockout of genes involved in the clock system, such as in Brain and Muscle Arnt-Like Protein-1 Ϫ/Ϫ , Clock Ϫ/Ϫ , and Steroid Receptor Coactivator-2 Ϫ/Ϫ mice, resulted in significant metabolic defects, including hepatic steatosis (20,51,57). Furthermore, chronic circadian disruption, for 52 wk, has been shown to cause hepatic steatosis (20).…”

Section: G937 Circadian Disruption Of Metabolismmentioning

confidence: 99%

“…For instance, knockout of genes involved in the clock system, such as in Brain and Muscle Arnt-Like Protein-1 Ϫ/Ϫ , Clock Ϫ/Ϫ , and Steroid Receptor Coactivator-2 Ϫ/Ϫ mice, resulted in significant metabolic defects, including hepatic steatosis (20,51,57). Furthermore, chronic circadian disruption, for 52 wk, has been shown to cause hepatic steatosis (20). In the current study, hepatic steatosis was induced in mice exposed to a RL cycle for only 8 wk, suggesting that the consequences of circadian disruption are relatively quick; however, further investigation on the time course of hepatic steatosis is required.…”

Section: G937 Circadian Disruption Of Metabolismmentioning

confidence: 99%

“…With the use of these models of shift work, it has been demonstrated that circadian misalignment promotes metabolic disturbances, such as obesity and impaired glucose metabolism (4,14,40,45,47). Furthermore, it has been demonstrated that chronic circadian disruption increases hepatic steatosis (20). The liver regulates many metabolic processes, including de novo lipogenesis, disruption of which could lead to lipid accumulation and hepatic steatosis.…”

Section: Introductionmentioning

confidence: 99%

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A rotating light cycle promotes weight gain and hepatic lipid storage in mice

Christie

Vincent

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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Processes involved in regulation of energy balance and intermediary metabolism are aligned to the light-dark cycle. Shift-work and high fat diet (HFD)-induced obesity disrupt circadian rhythmicity and are associated with increased risk of non-alcoholic fatty liver disease (NAFLD). This study aimed to determine the effect of simulating shift work on hepatic lipid accumulation in lean and HFD-mice. C57BL/6 mice fed a standard laboratory diet (SLD) or HFD for 4wks were further allocated to a normal light (NL)-cycle (lights on:0600-1800hr) or rotating light (RL)-cycle (3-days NL and 4-days reversed (lights on:1800-0600hr) repeated) for 8wks. Tissue was collected every 3hrs beginning at 0600hr. HFD-mice gained more weight than SLD-mice, and RL-mice gained more weight than NL-mice. SLD-NL and HFD-NL mice, but not RL-mice, were more active, had higher respiratory quotients and consumed/expended more energy during the dark phase compared to the light phase. Blood glucose and plasma cholesterol and triglyceride concentrations were elevated in HFD and SLD-RL compared to SLD-NL mice. Hepatic glycogen was elevated in HFD compared to SLD-mice. Hepatic triglycerides were elevated in SLD-RL and HFD-mice compared to SLD-NL. Circadian rhythmicity of hepatic acetyl-CoA carboxylase (ACACA) mRNA was phase shifted in SLD-RL and HFD-NL and lost in HFD-RL mice. Hepatic ACACA protein was reduced in SLD-RL and HFD-mice compared to SLD-NL mice. Hepatic adipose triglyceride lipase was elevated in HFD-NL compared to SLD-NL but lower in RL-mice compared to NL-mice irrespective of diet. -Conclusion: A RL-cycle model of shift-work promotes weight gain and hepatic lipid storage even in lean conditions.

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“…At least 10% of the liver transcriptome demonstrates rhythmic expression, implying that the circadian clock regulates a large set of hepatic genes [35]. It has been demonstrated that chronic circadian disruption promotes weight gain and hepatic lipid storage in mice [36,37]. This may be the reason for weight loss of liver and slight weight gain of body in our mouse model.…”

Section: Discussionmentioning

confidence: 76%

The effects of intermittent fasting on liver physiology and metabolism in mice

Chen

et al. 2020

Preprint

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Background: Intermittent fasting, as an emerging diet concept, has been widely practiced in the global population. A broad spectrum of health benefits has been reported in animal models and in humans for intermittent fasting. However, the underlying mechanisms remain largely elusive. In this study, we aimed to explore the effects and potential mode-of-action of intermittent fasting in mouse models, with focus on the liver.Methods: C57BL/6 mice were divided into five groups of 8-14 each, including 30-days ad libitum group, 30-days intermittent fasting group, 60-days ad libitum group, 60-days intermittent fasting group and refeeding group (30-days intermittent fasting followed by 30-days ad libitum). The food intake, body weight, liver weight and the blood biochemical parameters were detected. Targeted metabolic profiling of liver was performed.Results: We found that daily 12-hour intermittent fasting for one or two months significantly reduced the cumulative food intake, compared with the mice fed ad libitum. Fasting resulted in significantly reduced liver weight, with minimal effect on body weight. This effect on the liver by one month fasting could not be reversed by following one-month ad libitum feeding. Among the measured blood biochemical parameters, glucose level was decreased, while alkaline phosphatase was increased in the fasting mice. Surprisingly, targeted metabolic profiling revealed the global elevation of metabolites in the livers of fasting mice. These metabolic molecules include ATP, NADP, NADPH and succinate that are essentially involved in the citric acid cycle and oxidative phosphorylation. Conclusion: Daily 12-hour intermittent fasting for one to two months significantly reduced liver weight in mice, which is associated with enhanced liver metabolism.

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

Cited by 23 publications

References 56 publications

Oxysterols and Gastrointestinal Cancers Around the Clock

Oxysterols and Gastrointestinal Cancers Around the Clock

A rotating light cycle promotes weight gain and hepatic lipid storage in mice

The effects of intermittent fasting on liver physiology and metabolism in mice

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