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.
“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.
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.
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.
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.”