Liver cancer rates have tripled since the 1980s. Researchers now show that persistent sleep

deprivation in mice causes liver disease and eventually leads to liver cancer.
The study, by a team from Baylor College of Medicine in Texas, is published in the journal Cancer 
Cell.
“Recent studies have shown that more than 80 percent of the population in the United States
adopt a lifestyle that leads to chronic disruption in their sleep schedules,” notes Loning Fu, senior
author of the study and associate professor at Baylor College of Medicine.
“This has also reached an epidemic level in other developed countries, which is coupled with the increase in obesity and liver cancer risk,” she adds.
“Liver cancer is on the rise worldwide, and in human studies we’ve now seen that patients can
progress from fatty liver disease to liver cancer without any middle steps such as cirrhosis,” 
says co-lead author David Moore, professor of molecular and cellular biology.
“We knew we needed an animal model to examine this connection, and studies in the Fu Lab
found that chronically jet-lagged mice developed liver cancer in a very similar way as that 
described for obese humans,” he adds. 
Sleep disruption and liver cancer
The “master clock” in our brain regulates the circadian rhythms in tissues and organs around 
the body. This is important for sleep but also for normal metabolic function.
Shift work has already been linked to disruption of normal circadian function. A study reported by
Medical News Today earlier this year, for example, linked simulated shift working patterns in 
mice with increased development of nonsmall cell lung cancer.
Now, researchers have associated sleep disruption with increased risk of liver cancer.
The American Cancer Society report that 700,000 people worldwide are diagnosed with liver 
cancer each year. Men are more likely to develop liver cancer than women. In the U.S., they 
estimate that over 18,000 men and nearly 9,000 women will die in 2016 from liver cancer.
Obesity is a major risk factor for hepatocellular carcinoma (HCC) – the most common type of 
liver cancer. Excess fat in the liver results in nonalcoholic fatty liver disease (NAFLD), which 
has a high incidence rate in obese individuals. NAFLD has been predicted to become the 
major cause of HCC in the 21st century.
Jet-lagged mice developed liver cancer, HCC
To model the effect of chronic sleep disruption – or “social jet lag,” as the team describes it – 
mice were exposed to disrupted light and dark cycles for nearly 2 years, which resulted in 
prolonged disruption to their normal sleep cycles.
As a result, the mice developed a range of conditions, including skin disorders, 
neurodegeneration, and cancer. These were not seen in control mice, which had regular 
light and dark cycles. All mice received a normal diet.
Both male and female mice developed HCC by the age of 78 weeks, although, as in humans, 
the rates were much higher in males. Week 78 is equivalent to 67-72 years in human, which 
is when spontaneous development of HCC is mostly observed.
By the age of 90 weeks, 96 percent of jet-lagged mice had NAFLD, while almost 9 percent 
developed HCC around the same age.
Normal liver function was severely disrupted in the jet-lagged mice. Development of 
NAFLD was accompanied by severe inflammation and fibrosis prior to development of HCC.
Rodent gene expression patterns comparable to humans with HCC
When the researchers investigated global gene expression in the livers of jet-lagged mice, 
they found a pattern similar to that seen in humans with HCC.
This shows the direct effect that chronic jet lag has on gene expression, including genes 
involved in regulation of circadian rhythm (Bmal1, Clock, Per1, Per2 and Nr1d1), despite 
a lack of mutations in classic cancer genes.
Cholesterol and bile acid pathways, which are essential for normal liver function, were also 
disrupted. Nuclear receptor CAR, which is involved in sensing toxic compounds, was 
constitutively activated, while FXR, the bile acid receptor, was suppressed. This pattern is similar 
to HCC in humans.
“To us, our results are consistent with what we already knew about these receptors, but they 
definitely show that chronic circadian disruption alone leads to malfunction of these 
receptors.” Fu explains. “And thus, maintaining internal physiological homeostasis is really 
important for liver tumor suppression.”
The team concludes that HCC caused by disruption of normal liver function could be addressed 
by drugs which target these receptors.

“This experiment allowed us to take several threads that were already there and put them together 

to come to this conclusion. We think most people would be surprised to hear that chronic jet lag 
was sufficient to induce liver cancer.”
                                                                                                                                         David Moore