Circadian Dysregulation Disrupts Bile Acid Homeostasis

BACKGROUND:Bile acids are potentially toxic compounds and their levels of hepatic production, uptake and export are tightly regulated by many inputs, including circadian rhythm. We tested the impact of disrupting the peripheral circadian clock on integral steps of bile acid homeostasis. METHODOLOGY/PRINCIPAL FINDINGS:Both restricted feeding, which phase shifts peripheral clocks, and genetic ablation in Per1(-/-)/Per2(-/-) (PERDKO) mice disrupted normal bile acid control and resulted in hepatic cholestasis. Restricted feeding caused a dramatic, transient elevation in hepatic bile acid levels that was associated with activation of the xenobiotic receptors CAR and PXR and elevated serum aspartate aminotransferase (AST), indicative of liver damage. In the PERDKO mice, serum bile acid levels were elevated and the circadian expression of key bile acid synthesis and transport genes, including Cyp7A1 and NTCP, was lost. This was associated with blunted expression of a primary clock output, the transcription factor DBP, which transactivates the promoters of both genes. CONCLUSIONS/SIGNIFICANCE:We conclude that disruption of the circadian clock results in dysregulation of bile acid homeostasis that mimics cholestatic disease

Circadian dysfunction induces NAFLD-related human liver cancer in a mouse model.

BACKGROUND & AIMS: Chronic circadian dysfunction increases the risk of non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC), but the underlying mechanisms and direct relevance to human HCC have not been established. In this study, we aimed to determine whether chronic circadian dysregulation can drive NAFLD-related carcinogenesis from human hepatocytes and human HCC progression. METHODS: Chronic jet lag of mice with humanized livers induces spontaneous NAFLD-related HCCs from human hepatocytes. The clinical relevance of this model was analysed by biomarker, pathological/histological, genetic, RNA sequencing, metabolomic, and integrated bioinformatic analyses. RESULTS: Circadian dysfunction induces glucose intolerance, NAFLD-associated human HCCs, and human HCC metastasis independent of diet in a humanized mouse model. The deregulated transcriptomes in necrotic-inflammatory humanized livers and HCCs bear a striking resemblance to those of human non-alcoholic steatohepatitis (NASH), cirrhosis, and HCC. Stable circadian entrainment of hosts rhythmically paces NASH and HCC transcriptomes to decrease HCC incidence and prevent HCC metastasis. Circadian disruption directly reprogrammes NASH and HCC transcriptomes to drive a rapid progression from hepatocarcinogenesis to HCC metastasis. Human hepatocyte and tumour transcripts are clearly distinguishable from mouse transcripts in non-parenchymal cells and tumour stroma, and display dynamic changes in metabolism, inflammation, angiogenesis, and oncogenic signalling in NASH, progressing to hepatocyte malignant transformation and immunosuppressive tumour stroma in HCCs. Metabolomic analysis defines specific bile acids as prognostic biomarkers that change dynamically during hepatocarcinogenesis and in response to circadian disruption at all disease stages. CONCLUSION: Chronic circadian dysfunction is independently carcinogenic to human hepatocytes. Mice with humanized livers provide a powerful preclinical model for studying the impact of the necrotic-inflammatory liver environment and neuroendocrine circadian dysfunction on hepatocarcinogenesis and anti-HCC therapy. IMPACT AND IMPLICATIONS: Human epidemiological studies have linked chronic circadian dysfunction to increased hepatocellular carcinoma (HCC) risk, but direct evidence that circadian dysfunction is a human carcinogen has not been established. Here we show that circadian dysfunction induces non-alcoholic steatohepatitis (NASH)-related carcinogenesis from human hepatocytes in a murine humanized liver model, following the same molecular and pathologic pathways observed in human patients. The gene expression signatures of humanized HCC transcriptomes from circadian-disrupted mice closely match those of human HCC with the poorest prognostic outcomes, while those from stably circadian entrained mice match those from human HCC with the best prognostic outcomes. Our studies establish a new model for defining the mechanism of NASH-related HCC and highlight the importance of circadian biology in HCC prevention and treatment

Disrupting Circadian Homeostasis of Sympathetic Signaling Promotes Tumor Development in Mice

and why disruption of circadian rhythm may lead to tumorigenesis. oncogenic potential, leading to tumor development in the same organ systems in wild-type and circadian gene-mutant mice. is a clock-controlled physiological function. The central circadian clock paces extracellular mitogenic signals that drive peripheral clock-controlled expression of key cell cycle and tumor suppressor genes to generate a circadian rhythm in cell proliferation. Frequent disruption of circadian rhythm is an important tumor promoting factor

A Novel regulator of translation during early development of xenopus laevis

Bibliography: p. 168-198

Abstract A32: Studying circadian disruption as a novel risk factor of hepatocellular carcinoma using mouse models

Abstract Hepatocellular carcinoma (HCC) is previously considered a rare type of cancer in the Western world, but shows an annual increase of 3.5% since 1992 and is currently ranked second only to pancreatic cancer for cancer-related deaths in the United States due to its lack of early detection markers and poor prognosis. HCC is particularly difficult to treat because its development impairs liver normal drug metabolic function leading to chemoresistant. Although chronic infections with hepatitis B or C virus are the major risk factors for HCC worldwide, liver metabolic diseases associated with obesity such as non-alcoholic fatty liver diseases, diabetes mellitus and iron-storage diseases, account for the majority of HCC cases in the U.S. The rapid increase in obesity and obesity-associated metabolic disease in recent years suggests that the incidence of metabolic dysfunction-induced HCC is likely continually to increase in the States in the future. However, most existing HCC animal models develop tumors either following the treatment of carcinogens or ablation of a key liver tumor suppression pathway, which do not follow the same pathophysiological mechanisms of tumor initiation and progression as metabolic disorder-induced HCC in humans. Hence, there is a critical need to establish animal models that develop spontaneous HCC in response to chronic metabolic stress to study the mechanism of metabolic dysfunction-induced HCC, identify early detection markers associated with these types of HCC, and investigate the role of liver metabolic disruption in anticancer treatment. Most physiological processes including nutrient intake, storage and metabolism follows a circadian rhythm in mammals since our homeostatic systems are shaped by the evolutionary adaptation to daily light/dark changes in the environment. Disruption of circadian homeostasis leads to a coupled increase in the risk of obesity, liver metabolic syndromes and cancers in both night-shift human workers and animal models. We have previously reported that circadian gene-mutant mouse models show a significant increased risk to cancer. Our recent studies have revealed that disrupting circadian rhythm in wild-type mice by chronic jet-lag following a schedule that mimics the night-shift working schedules in humans leads to a progressive deregulation of multiple plasma and hepatic metabolic parameters in the serum and induction of multiple liver metabolic syndromes including hepatosteatosis as well as liver inflammation and uncontrolled hepatocytes and bile duct proliferation prior to HCC onset. Genome-wide array analyses have led to identify a time-dependent deregulation of all known key pathways controlling metabolism, energy storage, redox levels, cell proliferation, inflammatory response and tumor suppression in the liver of mice lacking circadian homeostasis. Our studies have established an excellent mouse model to study the role of metabolic dysfunction in spontaneous HCC induction. Further studies will lead to elucidate the mechanism of HCC induction by chronic metabolic disruption and identify novel serum and hepatic biomarkers for HCC early detection and treatment. Citation Format: Nicole M. Kettner, David D. Moore, Loning Fu. Studying circadian disruption as a novel risk factor of hepatocellular carcinoma using mouse models. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A32.</jats:p