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Hormone could be new target for fatty liver disease

Researchers may have found a new treatment target for treating fatty liver disease.

The researchers discovered that increasing the levels of the fat hormone Neuregulin 4 (Nrg4) protected liver cells from metabolic stress in mice. Loss of this hormone had the opposite effect; mouse livers deteriorated and progressed to nonalcoholic steatohepatitis, or NASH, more quickly.

“I think in the coming decades, it’s going to be a bigger problem than even diabetes…”

The findings led the researchers to believe that Nrg4 may be an effective target for therapeutic intervention.

Fatty liver disease represents a spectrum of disorders, ranging from relatively harmless benign fatty liver to potentially life-threatening NASH—which results in chronic inflammation, liver injury and fibrosis, increasing the risk of cirrhosis and liver cancer.

More than a third of US adults and up to 10 percent of children have some form of fatty liver disease. In up to 20 percent of these patients, the liver cells begin dying, and the disease develops into NASH. And the problem is growing.

“The estimate is that by 2020, NASH will be the leading cause of the need for liver transplants, surpassing hepatitis and alcoholic liver disease,” says senior author of the study and cell biologist Jiandie Lin, a faculty member at the University of Michigan’s Life Sciences Institute, where his lab is located, and at the university’s Medical School. “And there are currently no drugs available that can treat it.”

Despite this rising occurrence of fatty liver disease, scientists did not have a clear picture of what keeps cells healthy and stable under obesity-related stress in some patients, and what leads to cell death—and the progression to NASH—in others.

To address this question, Lin and his colleagues evaluated the effects of Nrg4 in mice that had been fed the type of high-fat, high-sugar diet that leads to fatty liver disease.

“When the hormone was elevated, we saw less cell death, less inflammation, less fibrosis,” says Liang Guo, a researcher in Lin’s lab and the lead author of the study. “On the other hand, mice lacking the hormone fare much worse. The hormone is having a distinct function that limits cell death and prevents progression to the most severe fatty liver disease.”

Drug might reverse liver damage from fatty foods

The findings expand on a previous study from Lin’s lab that showed Nrg4 could prevent the liver from converting sugar into fat, lowering the risk of fatty liver disease at its outset.

“We’re now seeing that it performs two major activities,” Lin says. “It not only regulates metabolism by reducing liver fat accumulation, but it’s also keeping the liver cells healthy. And by doing that, it can actually prevent the progression into NASH.”

And there’s more good news: The researchers have not yet seen any negative side-effects in the mice with increased Nrg4. Lin’s lab is now focused on further testing the therapeutic viability of the hormone in treating NASH.

The researchers report their findings in the Journal of Clinical Investigation.

The National Institutes of Health, the Michigan Diabetes Research Center, the Michigan Nutrition and Obesity Center, and Novo Nordisk supported the research.

Additional coauthors of the paper are from the University of Michigan; Northeast Ohio Medical University; and Novo Nordisk, Denmark.

Source: Emily Kagey for University of Michigan

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