Bile acids: New paper in *Science Advances*

As the interface between the digestive tract and the rest of the body, the liver is the most important central metabolic organ in the human body. An international team of researchers, which included scientists from the Medical University of Graz, has investigated nutrient signalling pathways within the liver and published its findings in the prestigious journal *Science Advances*. Specifically, the study focuses on how a particular nutrient signalling system alters the production of specific bile acids, which are linked to a range of key liver functions. A more detailed understanding of this could help to improve our understanding of metabolic liver diseases in the future.

Nutrient signals and immature liver cells

The liver precisely adapts its metabolism to the alternation between food intake and fasting. The mTORC1 protein complex plays a key role in this process: it acts as a central ‘nutrient sensor’ in liver cells and helps to regulate metabolism. A recent study, now published in the journal *Science Advances*, shows that this system not only influences fat and cholesterol metabolism, but also determines how stably liver cells maintain their specialised function.

The study focuses on proteins within the so-called LAMTOR/Ragulator complex. Their role is to link mTORC1 to the availability of nutrient signals such as amino acids, sugar or cholesterol. If certain components of this system—in the form of specific proteins—are inactivated in liver cells, these cells then exhibit genetic and metabolic characteristics more reminiscent of immature liver cells. At the same time, key processes involved in fat, cholesterol and bile acid metabolism are altered. These processes, and the associated loss of the liver’s detoxification and storage functions, can significantly drive the development of liver diseases or promote the development of hepatocellular carcinoma (liver cancer).

Consequences of altered bile acid metabolism

Changes in bile acids were particularly striking. The individual bile acids all differ in their structural composition and, consequently, in their properties, such as their toxicity or protective effects. The ratio of different bile acids to one another could therefore provide insights into what the liver is currently preparing for: the absorption and digestion of fats, or the activation or deactivation of certain metabolic processes. They thus act as signalling molecules that can influence metabolism throughout the body. The researchers observed that increased or decreased activity of mTORC1 significantly alters the ratio of different types of bile acids. “As the composition of dietary nutrients and metabolic hormones influences bile acid synthesis, it is conceivable that the regulation of liver metabolism is dynamically linked to changes in bile acid composition,” explains Tarek Moustafa from the Division of Gastroenterology and Hepatology at the Medical University of Graz.

In particular, so-called 12-hydroxylated bile acids came into focus. In mouse models with metabolic disorders, elevated levels of these bile acids were associated with specific changes in liver metabolism. In people with metabolic and adipose-related liver disease (MASLD, formerly often referred to as non-alcoholic fatty liver disease), evidence was also found of a link between the bile acid profile and metabolic changes such as insulin resistance.

A low-protein diet alters the ratio

The study also provides evidence that a lower-protein diet can influence the ratio of the bile acids under investigation. In both mice and people with MASLD, a reduced protein intake was associated with a lower proportion of 12-hydroxylated bile acids. Bile acids that do not belong to this group have been linked in previous studies to more favourable blood lipid levels, improved insulin sensitivity and positive effects in dietary interventions. Both a reduced protein intake (particularly the reduced intake of certain amino acids) and synthetic mTORC1 inhibitors (such as rapamycin) slow down cellular ageing. Interestingly, certain bile acids mimic the effects of fasting and influence cellular longevity in aged mice. Such ‘non-12-hydroxylated’ bile acids were found in notable concentrations in centenarians.

‘In cases of chronic overnutrition, a bile acid profile characterised by hyperactive mTORC1 may promote the liver cell dysfunction associated with insulin resistance in progressive MASLD. Conversely, an accumulation of non-12-hydroxylated bile acids, as observed with protein restriction, leads to beneficial metabolic effects. The reduced production of certain bile acids could therefore induce an energy-saving state that might potentially offer protection against prolonged overnutrition and metabolic liver diseases,” concludes Tarek Moustafa.

However, the researchers emphasise that many of the findings are initially based on animal models. Mice and humans differ significantly in their cholesterol and bile acid metabolism. Further clinical studies are therefore necessary before concrete dietary recommendations or therapeutic approaches for patients can be derived from the findings.

Profile: Tarek Moustafa

Tarek Moustafa completed his PhD at the Institute of Molecular Biosciences and now works in the Division of Gastroenterology and Hepatology at the Medical University of Graz, where he specialises in the regulatory role of bile acids in health and disease. His research focuses on how bile acids influence specific metabolic processes, and on the role of bile acid metabolism in various pathophysiological contexts, which is intended to contribute to a better understanding of the pathogenesis of metabolically-related liver diseases.

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