Medical

Experimental therapy reverses obesity-induced liver damage in mice

Experimental therapy reverses ...
A model of a liver with fatty liver disease, along with a microscope image of how the tissue looks
A model of a liver with fatty liver disease, along with a microscope image of how the tissue looks
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A model of a liver with fatty liver disease, along with a microscope image of how the tissue looks
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A model of a liver with fatty liver disease, along with a microscope image of how the tissue looks

Fatty liver disease is a condition linked to obesity and diabetes, and in turn often leads to further major complications. Researchers at the University of Southern California (USC) have now found a way to reverse the progression of the disease in mice, by quieting an overactive gene.

As the name suggests, the condition involves a build-up of fat in the liver. While one form of the disease is associated with excess alcohol intake, nonalcoholic fatty liver (NAFL) disease can be brought about through high-fat diets and is often associated with obesity. The condition can go on to cause damage to the organ, such as cirrhosis and liver cancer. Treatment options are currently limited, but for the new study the USC researchers say they’ve found a promising avenue in mouse tests.

In previous work, the team identified a protein called SAB that appeared to correlate with progression of NAFL disease – the stress of the excess fat activates a kinase enzyme that targets the SAB gene, which produces higher levels of the SAB protein. That in turn impairs mitochondrial function and increases reactive oxygen species, causing some of the damage.

So for the new study, the researchers investigated whether keeping the SAB gene from overproducing the protein could prevent damage to the liver. They started by feeding mice high-fat food pellets and sucrose and fructose water for a year, to induce obesity, diabetes and fatty liver diseases. The mice also received treatments of antisense oligonucleotides (ASO) – short synthetic DNA molecules that can temporarily silence genes. In the experimental group, mice received ASOs targeting the SAB gene, while a control group received placebo ASOs.

After 30 weeks, the control mice had developed steatohepatitis and fibrosis in the liver, which weren’t present in the group receiving the SAB-targeting ASOs. By the 52-week mark, those conditions had progressed in the control mice – but intriguingly, intervening with the ASO therapy from week 40 brought the unhealthy mice back to the level of mice that had just eaten regular non-high-fat chow.

“If we introduced this antisense targeting the liver cells, when the mice already had established disease with inflammation and fibrosis in the liver, we could reverse the entire thing, normalize their insulin resistance, and markedly decrease the fat accumulation in the liver and also the inflammation and fibrosis in the liver,” says Neil Kaplowitz, an author of the study.

While the results are intriguing, there’s of course no guarantee that mouse studies will carry across to humans. But the team is hopeful, because the SAB protein has been implicated in fatty liver disease in humans as well.

The research was published in the journal Hepatology.

Source: USC

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