Journal News

Liver enzyme holds key to adjusting to high-protein diets

Andrea Lius
Jan. 14, 2025

The Paleolithic diet mimics what human ancestors ate before the advent of agriculture. Doctors often prescribe this low-carbohydrate, high-protein diet for their prediabetic patients to help manage weight and glucose levels.

photo of prehistoric cave drawings

A recent study by Pierre Maechler’s group at the University of Geneva, published in the Journal of Biological Chemistry, investigated the role of the liver enzyme glutamate dehydrogenase, or GDH, in short-term adaptation to a high-protein diet.

“The question is how do we adapt when switching to a high-protein diet,” said Maechler. “In particular, what happens if you miss GDH, or if there’s something wrong with it?”

GDH, encoded by the gene GLUD1, is important in amino acid metabolism and gluconeogenesis, a biochemical pathway in the liver that synthesizes glucose from noncarbohydrate precursors. When food is present, the intestine is the main supplier of glucose to the brain, and gluconeogenesis in the liver halts. However, when a constant supply of glucose is unavailable, such as when people fast or partake in low-carbohydrate, high-protein diets, the liver takes over this responsibility by means of gluconeogenesis, mainly by breaking down amino acids from a replenishable source: skeletal muscles.

Maechler’s group initially studied GDH in pancreatic beta cells, which secrete insulin, then expanded their work to the brain and liver. In humans, Maechler explained, known GLUD1 mutations result in GDH gain of function and cause congenital hyperinsulinism/ hyperammonemia syndrome, or HI/HA.

Hyperinsulinism causes hypoglycemia, a severe condition for newborns that may hinder neurodevelopment. As they age, these children are prone to epilepsy and possible mental disabilities. On the other hand, an abnormally high level of ammonia in the blood, hyperammonemia, can be life-threatening. Because GDH gain-of-function mutations result in hyperammonemia, Maechler’s group expected that removing the enzyme would produce a low level of ammonia, or hypoammonemia – however, this was not the case.

“A surprising thing was when we knocked out GLUD1 in the liver; instead of experiencing hypoammonemia, the animals experienced hyperammonemia,” Maechler said, describing the genetically modified mice used in their past studies. “Basically, there’s this kind of bell-shaped effect of GDH function in terms of hyperammonemia.”

Maechler and colleagues also showed that a high-protein diet, coupled with the absence of liver GDH, causes hyperammonemia in mice and, consequently, high ammonia in the urine. This high level of ammonia made the blood more alkaline, and the mice had to significantly reduce their physical activity to maintain proper blood pH through compensatory slowed breathing, or hypoventilation.

“The mice can’t handle fasting periods as well without GDH,” Maechler said.

The researchers also found that while the expression of GDH is homogeneously distributed throughout the liver, the level of its activity is not. They monitored the GDH enzymatic activity in the liver using a nitro blue tetrazolium, or NBT, assay and found that GDH is significantly more active in the area near the central vein than near the portal vein.

By cryopreserving the liver and running the NBT assay on fresh liver tissue sections, Maechler explained, they obtained a close representation of what’s happening in a living animal.

In future studies, Maechler plans to investigate GDH function in prediabetic patients, who typically present with steatosis, or fatty livers.

“We showed that you need robust GDH activity to maintain a high-protein diet,” Maechler said.

“But when you have fatty liver, what does your GDH function look like? And can we still recommend a high-protein diet to these patients?”

Enjoy reading ASBMB Today?

Become a member to receive the print edition four times a year and the digital edition monthly.

Learn more
Andrea Lius

Andrea Lius is a Ph.D. candidate in the Ong quantitative biology lab at the University of Washington. She is an ASBMB Today volunteer contributor.

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

E-cigarettes drive irreversible lung damage via free radicals
Journal News

E-cigarettes drive irreversible lung damage via free radicals

April 17, 2025

E-cigarettes are often thought to be safer because they lack many of the carcinogens found in tobacco cigarettes. However, scientists recently found that exposure to e-cigarette vapor can cause severe, irreversible lung damage.

Using DNA barcodes to capture local biodiversity
ASBMB Annual Meeting

Using DNA barcodes to capture local biodiversity

April 15, 2025

Undergraduate at the University of California, Santa Barbara, leads citizen science initiative to engage the public in DNA barcoding to catalog local biodiversity, fostering community involvement in science.

Targeting Toxoplasma parasites and their protein accomplices
Journal News

Targeting Toxoplasma parasites and their protein accomplices

April 11, 2025

Researchers identify that a Toxoplasma gondii enzyme drives parasite's survival. Read more about this recent study from the Journal of Lipid Research.

Scavenger protein receptor aids the transport of lipoproteins
Journal News

Scavenger protein receptor aids the transport of lipoproteins

April 11, 2025

Scientists elucidated how two major splice variants of scavenger receptors affect cellular localization in endothelial cells. Read more about this recent study from the Journal of Lipid Research.

Fat cells are a culprit in osteoporosis
Journal News

Fat cells are a culprit in osteoporosis

April 11, 2025

Scientists reveal that lipid transfer from bone marrow adipocytes to osteoblasts impairs bone formation by downregulating osteogenic proteins and inducing ferroptosis. Read more about this recent study from the Journal of Lipid Research.

Unraveling oncogenesis: What makes cancer tick?
ASBMB Annual Meeting

Unraveling oncogenesis: What makes cancer tick?

April 7, 2025

Learn about the ASBMB 2025 symposium on oncogenic hubs: chromatin regulatory and transcriptional complexes in cancer.