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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Ancient herbivore's diet weakened teeth leading to eventual starvation, study suggests

A team of researchers from the University of Bristol have shed light on the life of the ancient reptile Rhynchosaur, which walked the earth between 250-225 million years ago, before being replaced by the dinosaurs.

Rhynchosaurs are a little-understood group of roughly sheep-sized ancient reptiles that thrived during the Triassic Period, a time of generally warm climates and tough vegetation.

In the new study, the researchers studied specimens found in Devon and used CT scanning to see how the teeth wore down as they fed, and how new teeth were added at the backs of the tooth rows as the animals grew in size.

The findings, published today in Palaeontology, show that these early herbivores likely eventually starved to death in old age, the vegetation taking its toll on their teeth.

"I first studied the rhynchosaurs years ago," said team-leader Professor Mike Benton from Bristol's School of Earth Sciences, "and I was amazed to find that in many cases they dominated their ecosystems. If you found one fossil, you found hundreds. They were the sheep or antelopes of their day, and yet they had specialized dental systems that were apparently adapted for dealing with masses of tough plant food."

Dr Rob Coram, who discovered the Devon fossils, said: "The fossils are rare, but occasionally individuals were entombed during river floods. This has made it possible to put together a series of jaw bones of rhynchosaurs that ranged in age from quite young, maybe even babies, through adults, and including one particularly old animal, a Triassic old-timer whose teeth had worn right down and probably struggled to get enough nutrition each day."

"Comparing the sequence of fossils through their lifetime, we could see that as the animals aged, the area of the jaws under wear at any time moved backwards relative to the front of the skull, bringing new teeth and new bone into wear," said Thitiwoot Sethapanichsakul who studied the jaws as part of his MSc in Palaeobiology. "They were clearly eating really tough food such as ferns, that wore the teeth down to the bone of the jaw, meaning that they were basically chopping their meals by a mix of teeth and bone."

"Eventually, though, after a certain age -- we're not sure quite how many years -- their growth slowed down and the area of wear was fixed and just got deeper and deeper," added Dr Coram. "It's like elephants today -- they have a fixed number of teeth that come into use from the back, and after the age of seventy or so they're on their last tooth, and then that's that.

"We don't think the rhynchosaurs lived that long, but their plant food was so testing that their jaws simply wore out and presumably they eventually starved to death."

The rhynchosaurs were an important part of the ecosystems on land during the Triassic, when life was recovering from the world's greatest mass extinction, at the end of the preceding Permian Period. These animals were part of this recovery and setting the scene for new types of ecologies when first dinosaurs, and later mammals became dominant, as the modern world was being slowly constructed.

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