Overeating and starving both damage the liver: Cavefish provide new insight into fatty liver disease

Fatty liver, which can lead to liver damage and disease, can occur from both overeating and starvation. Now, new research shows how naturally starvation-resistant cavefish, unlike other animals, are able to protect their liver and remain healthy. The findings have implications for understanding and potentially addressing liver conditions in humans.

Researchers from the Stowers Institute for Medical Research in collaboration with Universite Libre de Bruxelles in Belgium and Iowa State University compared cavefish to other animals more susceptible to starvation, and identified a gene responsible for the development of starvation-induced fatty liver.

The study, published in Life Science Alliance on March 11, 2024, led by co-first authors Ansa Cobham, Ph.D., in the lab of Associate Investigator Nicolas Rohner, Ph.D., and Macarena Pozo-Morales, Ph.D., in the lab of Assistant Professor Sumeet Pal Singh, Ph.D., also showed that this evolutionarily conserved gene can be targeted by an existing drug candidate to protect against liver damage.

"This same approach can be applied to what we see in overconsumption," Rohner said.

"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."

"We have discovered for the first time an organism -- cavefish -- that can avoid fatty liver under starvation conditions," said Cobham.

"Fatty liver can result in complications like liver cirrhosis and liver failure. This study helps us understand more about the biology underlying these diseases in humans."

Cavefish are cousins of the Mexican tetra river fish that flooded into underground caves over 100,000 years ago.

The researchers show that in the absence of food, cavefish at early developmental stages not only survive much longer than their river fish counterparts, but also do not accumulate liver fat.

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

The accumulation of fat in liver cells leads to organ damage and atrophy or wasting away.

The researchers compared gene expression levels between cavefish, river fish, zebrafish, and even fruit flies, identifying a gene that is activated during prolonged periods of starvation in all but cavefish.

"Expression levels of this gene are reduced in cavefish, which is a good indicator that if we are able to target this gene in humans, we may be able to treat or manage human metabolic diseases such as Type 2 diabetes and obesity," said Cobham.

The team's findings indicate that the starvation-induced gene not only regulates fatty liver disease, but its mechanism has also been conserved from fruit flies to fish to humans, or approximately 400 million years of animal evolution.

Inhibiting this gene's protein in zebrafish and river fish larvae and deleting the gene in fruit flies resulted in less liver fat and larger livers indicating this protects the liver from damage and atrophy.

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From cavefish to humans: Evolution of metabolism in cavefish may provide insight into treatments for a host of diseases such as diabetes, heart disease, and stroke

New research from the Stowers Institute for Medical Research examines how cavefish, surface-dwelling river fish that flooded into underground cave systems over 100,000 years ago, developed unique metabolic adaptations to survive in nutrient-scarce environments. The study, published online in Nature Genetics on May 12, 2022, led by Jaya Krishnan, PhD, a senior research associate in the lab of Nicolas Rohner, PhD, created a genome-wide map of liver tissue for two independent colonies of cavefish along with river fish to understand how cavefish metabolism evolved and how this may be applicable for humans.

Historically, humans have been able to adapt during periods of feast or famine. Today, however, feast has replaced famine in many regions around the globe leading to a rise in a host of diseases related to metabolism such as diabetes, heart disease and stroke. Collectively called metabolic syndrome, these conditions are associated with genetic mutations in regions of DNA that regulate how our genes work to keep us healthy; on an evolutionary timescale, the constant "feast state" is in its infancy, which for humans, means disease rather than adaptation.

This study marks the first time genetic mapping of the non-coding regions of liver DNA that act to regulate gene activity and expression have been performed. The new data is a now valuable resource for the scientific community studying starvation resistance and metabolism.

"It's a very good foundation for us or anyone to now ask relevant questions in relation to metabolism, diet, and adaptation," said Krishnan.

Metabolism, or the way in which we utilize and store energy, is an integral part of health in all species. Cavefish are ideal for studying metabolism; during periodic flooding of caves, these fish intake and store all the nutrition they need to survive until the next nutrient inundation, which may not be for another year. "They can shed light on metabolic disorders such as diabetes and obesity," said Krishnan, because, despite elevated fat and blood glucose levels, these fish remain vibrant and healthy.

"The fact that these fish are apparently healthy, despite having these extreme traits is, by definition, a good place to ask how they deal with that," said Rohner.

What is truly remarkable is that the two independently derived cavefish colonies examined in this study evolved strikingly similar metabolic adaptations to survive in dark, nutrient-scarce environments. This raises the question, what can we learn from animals who have had the time to evolve? And even further, if multiple cavefish populations evolved in a very similar manner completely independently from each other, are there universal adaptation mechanisms that could potentially be triggered in other species like humans?

"We know only a handful of genes that could be therapeutic targets," said Krishnan. "This means we need to adopt novel ways to identify such potential genes so that we can investigate them, and cavefish are a very powerful system for us to do that."

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