Fish defense mechanism may reveal fatty liver disease therapeutic target

Cave-dwelling fish resistant to gene activation in response to starvation

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A possible therapeutic target for fatty liver disease (FLD) has been identified by researchers studying the natural defense mechanisms of certain cave-dwelling fish.

While nutritional deprivation led to FLD in their relatives, these fish were able to protect their own livers from similar damage. This was attributed to lower activity of a gene called slc27a2a in response to starvation.

“We have discovered for the first time an organism — cavefish — that can avoid fatty liver under starvation conditions,” Ansa Cobham, PhD, one of the study’s first authors at the Stowers Institute for Medical Research in Missouri, said in an institute press release.

While the findings suggest targeting this gene may offer a strategy for preventing or treating starvation-induced FLD, “this same approach can be applied to what we see in overconsumption,” said Nicolas Rohner, PhD, one of the study’s senior author at the Stowers Institute and the University of Kansas Medical Center. “In Western societies where, often, too many calories and not enough exercise is a problem, this new understanding may lead to prevention or potential treatment of fatty liver disease.”

The study, “Starvation-resistant cavefish reveal conserved mechanisms of starvation-induced hepatic lipotoxicity,” was published in Life Science Alliance.

In fatty liver disease, now known as steatotic liver disease, fatty deposits accumulate in the liver — called steatosis — and can lead to liver inflammation and scarring that permanently damage it.

Overeating, associated with obesity, diabetes, and high blood cholesterol, among other health problems, contributes to FLD development, and diet is considered a critical part of managing the disease. But starvation can also significantly compromise liver health and induce fatty liver deposits to accumulate.

“Though considerable attempts are being made to develop interventions aimed at protecting the liver from lipotoxicity [fat-related toxicity] in response to high-fat diet or obesity … interventions to protect the liver during starvation are nonexistent,” the researchers wrote.

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Starvation resistance in cave-dwelling fish

Finding protective mechanisms animals use to cope with starvation in their natural environment is one way to identify new treatment approaches.

Astyanax mexicanus, or the Mexican tetra, is found in the waters near Mexico. While surface fish in rivers have consistent access to food, a variety of cave-dwelling A. mexicanus have adapted to a nutrient-poor underground environment.

The researchers found that cavefish larvae were naturally starvation-resistant, surviving much longer than their surface fish relatives when deprived of food early in development. And while liver fat deposit accumulation and liver tissue wasting occur in surface fish, cavefish avoid these starvation-induced complications.

“This was the first time we clearly showed that the mechanism for this [starvation] resistance is accomplished by not accumulating excess fat in the liver,” Rohner said.

The scientists took a deeper dive to identify possible protective strategies in the cavefish that could be leveraged for treating fatty liver disease.

Gene activity analyses showed the slc27a2a gene, which encodes the production of SLC27A2, a fat transporter protein, was activated in surface fish and a type of fish called zebrafish in response to starvation, but not in cavefish.

The scientists believe the increase in slc27a2a activity facilitates the uptake of fats in liver cells to contribute to liver damage during fasting, but cavefish are protected because the gene doesn’t ramp up its activity as it does in other fish. Indeed, blocking SLC27A2 in zebrafish or surface fish with a molecule called lipofermata led to reductions in fat deposits in the liver and an increase in its size.

It also increased activity of genes related to cell growth, which could help the liver resist wasting away, and decreased gene activity related to inflammatory signaling. Still, it didn’t make the fish entirely starvation-resistant as in the cavefish.

In fruit flies, an animal model commonly used for genetic studies, reductions of the gene’s activity in liver cells again reduced starvation-induced steatosis. That such effects are observed across multiple species suggested “the evolutionarily conserved importance of the gene in regulating fatty liver upon nutrition deprivation,” the researchers wrote.

“This study helps us understand more about the biology underlying these diseases in humans,” Cobham said, adding that “if we are able to target this gene … we may be able to treat or manage human metabolic diseases such as Type 2 diabetes and obesity.”