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Reversing a common liver disease

People with nonalcoholic fatty liver disease develop excess fat in the liver, illustrated here, even though they drink little or no alcohol. The arrow points to an old cell filled with fat.Newcastle University

Fatty liver disease is the abnormal accumulation of fat in liver cells. It can result from heavy alcohol use or other sources of liver injury. Fatty liver disease in people who don’t drink alcohol, called nonalcoholic fatty liver disease (NAFLD), is the most common cause of long-term liver disease in the US. The exact reasons are unknown, but NAFLD is more common in people with obesity and diabetes.

The initial stage of fatty liver disease is steatosis, which usually doesn’t cause symptoms but can worsen to life-threatening liver diseases, such as liver cancer. The primary treatment for NAFLD is a healthy diet and physical activity to manage diabetes and reduce body weight. If the disease worsens, a liver transplant may be needed.

As people age, old or damaged cells stop dividing to produce new cells. Over time, these “senescent” cells accumulate in the liver and other tissues. Previous studies have linked such cells to certain age-related diseases.

A team of international researchers led by Dr. Diana Jurk of Newcastle University in the UK explored whether senescent cells play a role in NAFLD. Groups led by Drs. James Kirkland of Mayo Clinic in Rochester and Jan Hoeiimakers of Erasmus Medical Centre in the Netherlands collaborated on the study. The work was supported in part by NIH’s National Institute on Aging (NIA). Results were published in Nature Communications on June 13, 2017.

The researchers found that mice with a restricted diet usually didn’t have fatty livers, whereas mice with an unrestricted diet did. Those fed an unrestricted diet had more molecular markers of senescence in liver cells as they aged. Diet restriction protected mice from these signs of senescence.

Next, using two different methods, the team showed that eliminating senescent cells in middle-aged mice reduced the level of fat in the liver. One involved genetically modified mice that enabled the researchers to selectively eliminate senescent cells. The other used recently discovered drugs, called , that kill senescent cells. These drugs also reduced the level of fat in the liver in a mouse model of type 2 diabetes and liver steatosis.

The team found that senescent cells were poor at metabolizing fatty acids. This suggests that senescent cells may have faulty mitochondria, the power plants of the cell that normally metabolize fatty acids. The finding could explain why fat collects in these cells.

In liver tissue samples from people with NAFLD, the researchers found that fat accumulation was tied to an increase in senescence markers. Taken together, these results suggest that senescent liver cells may be a factor underlying NAFLD.

“As we age, we accumulate cell damage, and we have shown that these older cells are storing excess fat due to their inefficient mitochondria,” Jurk says. “What is exciting is that we have been able to reverse this damage in mice by removing these older, worn-out cells.”

Researchers continue to explore the idea of ridding the body of senescent cells. However, the approach will require careful study because it could have unexpected side effects.

—by Geri Piazza