Reference SummaryKettner NM, Cancer Cell 2016 Dec 12;30(6):909-924

Title

Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis.

Authors

Kettner NM; Voicu H; Finegold MJ; Coarfa C; Sreekumar A; Putluri N; Katchy CA; Lee C; Moore DD; Fu L

Journal

Cancer Cell

Volume

30

Issue

6

Year

2016

Pages

909-924

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.

Links

J:237981 – Mouse Genome Informatics
27889186 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6J Leukocyte - Lymphocyte - B-lymphocyte tumor
  • jet-lag light cycle
Leukocyte - Lymphocyte - B-lymphocyte

observed

B6.129-Per1tm1Brd Per2tm1Ccl Leukocyte - Lymphocyte - B-lymphocyte tumor
  • jet-lag light cycle
Leukocyte - Lymphocyte - B-lymphocyte

observed

B6.129P2-Cry1tm1Asn Cry2tm1Asn Leukocyte - Lymphocyte - B-lymphocyte tumor
  • jet-lag light cycle
Leukocyte - Lymphocyte - B-lymphocyte

observed

B6.Cg-Arntltm1Weit Speer6-ps1Tg(Alb-cre)21Mgn/? Leukocyte - Lymphocyte - B-lymphocyte tumor
  • jet-lag light cycle
Leukocyte - Lymphocyte - B-lymphocyte

observed

B6.129-Per1tm1Brd Per2tm1Ccl Leukocyte - Lymphocyte - B-lymphocyte tumor Leukocyte - Lymphocyte - B-lymphocyte

observed

B6.129P2-Cry1tm1Asn Cry2tm1Asn Leukocyte - Lymphocyte - B-lymphocyte tumor Leukocyte - Lymphocyte - B-lymphocyte

observed

B6.Cg-Arntltm1Weit Speer6-ps1Tg(Alb-cre)21Mgn/? Leukocyte - Lymphocyte - B-lymphocyte tumor Leukocyte - Lymphocyte - B-lymphocyte

observed

C57BL/6J Liver hepatocellular carcinoma Liver

0

C57BL/6J Liver hepatocellular carcinoma
  • jet-lag light cycle
Liver

observed - 8.75

B6.129P2-Cry1tm1Asn Cry2tm1Asn Liver hepatocellular carcinoma Liver

observed - 11.67

B6.129P2-Cry1tm1Asn Cry2tm1Asn Liver hepatocellular carcinoma
  • jet-lag light cycle
Liver

observed - 17.86

B6.129-Per1tm1Brd Per2tm1Ccl Liver hepatocellular carcinoma Liver

observed - 12.5

B6.129-Per1tm1Brd Per2tm1Ccl Liver hepatocellular carcinoma
  • jet-lag light cycle
Liver

observed - 20

B6.Cg-Arntltm1Weit Speer6-ps1Tg(Alb-cre)21Mgn/? Liver hepatocellular carcinoma Liver

observed - 11.54

B6.Cg-Arntltm1Weit Speer6-ps1Tg(Alb-cre)21Mgn/? Liver hepatocellular carcinoma
  • jet-lag light cycle
Liver

observed - 11.63

C57BL/6J-Nr1i3tm1Ddm Liver hepatocellular carcinoma Liver

0

C57BL/6J-Nr1i3tm1Ddm Liver hepatocellular carcinoma
  • jet-lag light cycle
Liver

0

C57BL/6J-Nr1h4tm1Gonz Liver hepatocellular carcinoma Liver

28

C57BL/6J-Nr1h4tm1Gonz Liver hepatocellular carcinoma
  • jet-lag light cycle
Liver

61.29

C57BL/6J Liver hyperplasia Liver

15.45

C57BL/6J Liver hyperplasia
  • jet-lag light cycle
Liver

75

B6.129P2-Cry1tm1Asn Cry2tm1Asn Liver hyperplasia Liver

68.33

B6.129P2-Cry1tm1Asn Cry2tm1Asn Liver hyperplasia
  • jet-lag light cycle
Liver

69.64

B6.129-Per1tm1Brd Per2tm1Ccl Liver hyperplasia Liver

86.25

B6.129-Per1tm1Brd Per2tm1Ccl Liver hyperplasia
  • jet-lag light cycle
Liver

86

B6.Cg-Arntltm1Weit Speer6-ps1Tg(Alb-cre)21Mgn/? Liver hyperplasia Liver

73.08

B6.Cg-Arntltm1Weit Speer6-ps1Tg(Alb-cre)21Mgn/? Liver hyperplasia
  • jet-lag light cycle
Liver

95.35

C57BL/6J-Nr1i3tm1Ddm Liver hyperplasia Liver

25

C57BL/6J-Nr1i3tm1Ddm Liver hyperplasia
  • jet-lag light cycle
Liver

0

C57BL/6J-Nr1h4tm1Gonz Liver hyperplasia Liver

100

C57BL/6J-Nr1h4tm1Gonz Liver hyperplasia
  • jet-lag light cycle
Liver

100

C57BL/6J Ovary tumor
  • jet-lag light cycle
Ovary

observed

B6.129-Per1tm1Brd Per2tm1Ccl Ovary tumor
  • jet-lag light cycle
Ovary

observed

B6.129P2-Cry1tm1Asn Cry2tm1Asn Ovary tumor
  • jet-lag light cycle
Ovary

observed

B6.Cg-Arntltm1Weit Speer6-ps1Tg(Alb-cre)21Mgn/? Ovary tumor
  • jet-lag light cycle
Ovary

observed

B6.129-Per1tm1Brd Per2tm1Ccl Ovary tumor Ovary

observed

B6.129P2-Cry1tm1Asn Cry2tm1Asn Ovary tumor Ovary

observed

B6.Cg-Arntltm1Weit Speer6-ps1Tg(Alb-cre)21Mgn/? Ovary tumor Ovary

observed

C57BL/6J Pancreas tumor
  • jet-lag light cycle
Pancreas

observed

B6.129-Per1tm1Brd Per2tm1Ccl Pancreas tumor
  • jet-lag light cycle
Pancreas

observed

B6.129P2-Cry1tm1Asn Cry2tm1Asn Pancreas tumor
  • jet-lag light cycle
Pancreas

observed

B6.Cg-Arntltm1Weit Speer6-ps1Tg(Alb-cre)21Mgn/? Pancreas tumor
  • jet-lag light cycle
Pancreas

observed

B6.129-Per1tm1Brd Per2tm1Ccl Pancreas tumor Pancreas

observed

B6.129P2-Cry1tm1Asn Cry2tm1Asn Pancreas tumor Pancreas

observed

B6.Cg-Arntltm1Weit Speer6-ps1Tg(Alb-cre)21Mgn/? Pancreas tumor Pancreas

observed

C57BL/6J (Unspecified organ) tumor (Unspecified organ)

0

C57BL/6J (Unspecified organ) tumor
  • jet-lag light cycle
(Unspecified organ)

observed

B6.129P2-Cry1tm1Asn Cry2tm1Asn (Unspecified organ) tumor (Unspecified organ)

observed

B6.129P2-Cry1tm1Asn Cry2tm1Asn (Unspecified organ) tumor
  • jet-lag light cycle
(Unspecified organ)

observed

B6.129-Per1tm1Brd Per2tm1Ccl (Unspecified organ) tumor (Unspecified organ)

observed

B6.129-Per1tm1Brd Per2tm1Ccl (Unspecified organ) tumor
  • jet-lag light cycle
(Unspecified organ)

observed

B6.Cg-Arntltm1Weit Speer6-ps1Tg(Alb-cre)21Mgn/? (Unspecified organ) tumor (Unspecified organ)

observed

B6.Cg-Arntltm1Weit Speer6-ps1Tg(Alb-cre)21Mgn/? (Unspecified organ) tumor
  • jet-lag light cycle
(Unspecified organ)

observed