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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #337749
Title: Circadian homeostatis of liver metabolism suppresses hepatocarcinogenesis

Author
item KETTNER, NICOLE - Children'S Nutrition Research Center (CNRC)
item VOLCU, HORATIO - Baylor College Of Medicine
item FINEGOLD, MILTON - Baylor College Of Medicine
item COARFA, CRISTIAN - Baylor College Of Medicine
item SREEKUMAR, ARUN - Baylor College Of Medicine
item PUTLURI, NAGIREDDY - Baylor College Of Medicine
item KATCHY, CHINENYE - Children'S Nutrition Research Center (CNRC)
item LEE, CHOOGON - Florida State University
item MOORE, DAVID - Baylor College Of Medicine
item FU, LONING - Children'S Nutrition Research Center (CNRC)

Submitted to: Cancer Cell International
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/11/2016
Publication Date: 12/12/2016
Citation: Kettner, N.M., Volcu, H., Finegold, M.J., Coarfa, C., Sreekumar, A., Putluri, N., Katchy, C.A., Lee, C., Moore, D.D., Fu, L. 2016. Circadian homeostatis of liver metabolism suppresses hepatocarcinogenesis. Cancer Cell International. 30:909-924.

Interpretive Summary: Obesity-related non-alcoholic fatty liver disease (NAFLD) has been identified as a novel risk factor for increased risk of hepatocellular carcinoma (HCC) in the U.S., coupled with the prevalence of NAFLD and epidemics of chronic circadian disruption. Our studies demonstrate that chronic circadian disruption in normal mice can induce NAFLD-related HCC following similar molecular and pathophysiological mechanisms as those observed in obese human subjects. We demonstrated that the nuclear receptor CAR, plays a key role in stimulating circadian disruption-induced hepatocarcinogenesis. HCC is currently the fastest rising cause of cancer related death in the U.S. due to a lack of understanding of its mechanism and therapeutic targets. Our findings have made a significant leap forward by establishing an animal model for further studying the mechanism of obesity-related HCC, and by identifying nuclear receptor CAR as a novel therapeutic target for prevention of metabolic syndrome-induced HCC.

Technical Abstract: Chronic jet lag induces spontaneous hepatocellular carcinoma (HCC) in wild-type mice following a mechanism very similar to that observed in obese humans. The process initiates with non-alcoholic fatty liver disease (NAFLD) that progresses to steatohepatitis and fibrosis before HCC detection. This pathophysiological pathway is driven by jet-lag-induced genome-wide gene deregulation and global liver metabolic dysfunction, with nuclear receptor-controlled cholesterol/bile acid and xenobiotic metabolism among the top deregulated pathways. Ablation of farnesoid X receptor dramatically increases enterohepatic bile acid levels and jet-lag-induced HCC, while loss of constitutive androstane receptor (CAR), a well-known liver tumor promoter that mediates toxic bile acid signaling, inhibits NAFLD-induced hepatocarcinogenesis. Circadian disruption activates CAR by promoting cholestasis, peripheral clock disruption, and sympathetic dysfunction.