Chronic Jet Lag Promotes Metabolic Dysfunction and Hepatocarcinogenesis

Circadian dysfunction increases the risk of metabolic disorders, nonalcoholic fatty liver disease (NAFLD), and hepatocellular carcinoma in night-shift workers. Further, in mice, deletion of key circadian clock genes can accelerate tumorigenesis. To determine if chronic circadian disruption is sufficient to induce spontaneous hepatocellular carcinoma via liver metabolic dysfunction, Kettner and colleagues evaluated mice under jet-lagged conditions compared with steady 24-hour light/dark cycles. The jet-lagged mice exhibited reduced survival and increased development of hepatocellular carcinoma and accelerated tumor progression. Examination of livers from jet-lagged mice revealed early onset NAFLD, altogether indicating that circadian disruption can induce NAFLD and spontaneous hepatocellular carcinoma in mice. The jet-lagged mice also developed metabolic syndrome, exhibiting increased hepatic triglycerides and free fatty acids, reduced serum triglycerides, insulin resistance, and decreased hepatic glycogen storage. This was accompanied by liver damage and inflammation, accelerated hepatocyte proliferation and death, and fibrosis that preceded the development of hepatocellular carcinoma. Metabolic profiling of control mice showed a circadian rhythm for most metabolites that was disrupted in jet-lagged mice, and the metabolic profiles induced by chronic jet lag indicated an acceleration of cytoplasmic glycolysis resulting in a shift in liver metabolism toward lipid synthesis and storage. Moreover, chronic jet lag induced genome-wide changes in gene expression, inducing a gene signature similar to that of human hepatocellular carcinoma, and deregulating key circadian genes, suggesting that jet lag can disrupt the liver clock independent of mutations in circadian rhythm genes. The xenobiotic constitutive androstane receptor (CAR), known to promote liver cancer in mice and to be highly expressed in human hepatocellular carcinoma, was found to be a clock-controlled gene activated by jet lag, and was required for the progression from NAFLD to hepatocellular carcinoma. These results indicate that chronic jet lag is sufficient to disrupt hepatic gene expression and metabolism to drive NAFLD and spontaneous hepatocarcinogenesis.

Kettner NM, Voicu H, Finegold MJ, Coarfa C, Sreekumar A, Putluri N, et al. Circadian homeostasis of liver metabolism suppresses hepatocarcinogenesis. Cancer Cell 2016;30:909–24.

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