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New research has helped unravel the role of a key molecule in cholestatic liver disease

23 December 2021

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Researchers from the Quadram Institute, University of East Anglia and Technische Universität Braunschweig found that, in mice, a key metabolic regulator triggers cells in the immune system to attack liver cells, progressing the disease.

Uncovering the role of this molecule, called SIRT 1, opens up new avenues of research to develop therapies to tackle the condition in humans.

Cholestatic liver disease is a spectrum of conditions characterised by an accumulation of bile acids in the liver, leading to liver damage.

Bile is a fluid produced by the liver that is used to digest fats and remove waste products from the body. It drains from the liver via bile ducts. In cholestatic liver disease, the bile ducts become damaged or blocked, which in turn leads to liver failure, inflammation, fibrosis and ultimately to cancer. The exact triggers aren’t known, but it’s believed to be linked to the immune system, and in some forms is considered an autoimmune disease.

Treatment options are limited and aren’t always effective against the main forms of cholestatic liver disease, primary biliary cholangitis and primary sclerosing cholangitis. For primary sclerosing cholangitis, other treatments are showing promise in trials, but to develop highly effective novel treatments a clearer understanding of the causes of the condition, at the molecular level, is needed

This has been the subject of the research of Dr Naiara Beraza and her team from the Quadram Institute on the Norwich Research Park. They have focused on a key metabolic regulator called Sirtuin 1 (SIRT1). SIRT1 has been hailed as a “magic bullet” apparently able to prolong lifelong health, regulate inflammation and boost metabolism – there are even SIRTFood diets that claim to target these genes to help you lose weight. Whilst this may all have been overhyped, what is clear is that SIRT1 plays a central role in many biological processes, but how it controls these is highly complex.

Dr Beraza and others have previously shown that SIRT1 is involved in liver disease and in impairing liver regeneration.

Working with Dr Stuart Rushworth from UEA’s Norwich Medical School and Prof Dr Karsten Hiller from the Technische Universität Braunschweig in Germany, they have defined how SIRT1 activates macrophages. These are key cells of the immune system that promote inflammation, damaging the liver.

The study was published recently in the leading journal Cellular and Molecular Gastroenterology and Hepatology, and funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and Medical Research Council, part of UKRI, the Wellcome trust and the BBSRC Doctoral Training Partnership.

By performing studies in preclinical mouse models, the team showed that SIRT1 is upregulated in inflammatory cells (macrophages) in this condition. The overexpression of SIRT1 leads to a metabolic rewiring of the macrophages in a way that triggers inflammation, attacking the liver cells, and contributing to the progression of the disease.

The trigger for this SIRT1 upregulation appears to be a combination of liver cell death due to altered levels of bile acids, which is what is seen when bile ducts are damaged, and the increased flow of bacterial products into the liver from a more permeable intestine.

In contrast to the view that SIRT1 has anti-inflammatory properties, the team has established its pro-inflammatory and damaging action in the liver during cholestatic disease.

“Looking at our findings from this study and others we have published, we suggest that fine-tuning the levels of SIRT1 are what is crucial to maintaining liver health, rather than blocking its action completely” said Dr Beraza.

“Our research shows that there are certainly no “magic bullets” in the search for new therapies to treat cholestatic disease”

“However, we hope that our findings will start to unravel some of the complexity involved and point the way towards much-needed treatments in the future.”

Reference: Metabolic regulation of macrophages by SIRT1 determines activation during cholestatic liver disease in mice, Anna Isaacs-Ten, Mar Moreno-Gonzalez, Caitlin Bone, Andre Martens, Federico Bernuzzi, Tobias Ludwig, Charlotte Hellmich, Karsten Hiller, Stuart A. Rushworth, Naiara Beraza. Cellular and Molecular Gastroenterology and Hepatology.

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