The research was led by Prof Stuart Cook (right), Tanoto Foundation Professor of Cardiovascular Medicine and Director of National Heart Research Institute of Singapore, NHCS, together with Asst Prof Sebastian Schäfer (left), Senior Research Fellow from NHCS.

Breakthrough translational research paves way for the development of world’s first thorough drug target.

Researchers from the NHCS and Duke-NUS Medical School have found that deactivating a specific protein − interleukin 11 (IL11) – with drugs called therapeutic antibodies, helps reverse inflammation and scarring of the liver in patients suffering from an untreatable type of fatty liver disease, called Non-Alcoholic Steatohepatitis (NASH).

The liver plays a key role in breaking down and storing glucose and fat. In conditions such as Non-alcoholic Fatty Liver Disease (NAFLD), too much fat is stored in the liver. NAFLD, also commonly known as ‘fatty liver’, is a liver disorder and refers to a group of conditions where there is accumulation of excess fats in the livers of people who drink little or no alcohol.

The disease can progress to liver inflammation, fibrosis and NASH. NASH refers to liver inflammation and damage caused by a build-up of fat in the liver. It causes fatigue, abdominal pain, itchy skin, nausea, and can lead to liver cirrhosis. Those with diabetes and obesity are particularly at risk, and people who are slim may still be predisposed to having fatty liver disease, particularly for Asians. There is currently no treatment available for both NAFLD and NASH, whereby drugs tested previously have failed to work.

Fatty liver disease is fast becoming a global pandemic, affecting approximately one in four around the world. In Singapore, it is even more common, affecting up to one in three – even found in patients who are slim.

While fatty liver disease can be tolerated if it is not severe, it may worsen over time, resulting in the fatty liver becoming inflamed, fibrotic and scarred, and even leading to liver failure and cancers.

fatty liver disease progression
(Click on the image to expand)

The condition is also linked to insulin resistance which can cause raised blood sugars, as well as high blood cholesterol and triglycerides. Insulin resistance, obesity, high cholesterol and triglycerides are categorised as cardiometabolic disorders that are inter-related and can increase the risk of cardiovascular disease and Type 2 diabetes.

Root of the problem

What causes fatty liver disease? A main attribution is over nutrition from the food eaten, which boils down to not just what one consumes, but also the type of food eaten, such as fatty food and high sugar drinks. With a growing ’fast food’ trend, fatty liver disease has become a major health concern, as even children are now diagnosed with fatty liver and NASH.

More significantly, the research team discovered that the IL11 gene triggers the development of NASH and fat accumulates in the livers of people with the condition. IL11 is a critical protein that causes fibrosis and organ damage, which was initially thought to be anti-fibrotic until the same team of researchers overturned this misconception in 2017.

MRI scan for fatty liver
An MRI scan of liver fat, inflammation and fibrosis. 

The team found that this protein is very important for fat accumulation, scarring and inflammation of the liver processes, and inhibiting IL11 not only can prevent fatty liver disease, but also reverse the condition after it has taken hold of the liver.

Hope for new treatment modality

The therapeutic antibodies developed by NHCS and Duke-NUS researchers has shown to inhibit IL11 in a pre-clinical model that mimicked the human formof NASH, preventing and reversing liver inflammation, and even lowering blood levels of cholesterol and glucose.

“We identified a new approach to treat these patients and restore their liver function, while lowering the dangerous fats and glucose in their blood,” added Prof Stuart Cook, corresponding author of the research study, who is the Tanoto Foundation Professor of Cardiovascular Medicine and the Director of National Heart Research Institute of Singapore and Senior Consultant from Department of Cardiology at NHCS.

Prof Cook is also the Director and CoFounder of Enleofen Bio, a biotechnology company established in Singapore that is now developing the antibody therapeutics for clinical trials. The drugs are aimed to be ready for clinical trials by the end of 2020.

The findings1 were published in the top journal for liver and gut diseases, Gastroenterology.

IL11 effect on liver
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 1Inhibiting Interleukin 11 Signaling Reduces Hepatocyte Death and Liver Fibrosis, Inflammation, and Steatosis in Mouse Models of Non-Alcoholic Steatohepatitis. Gastroenterology. DOI: 10.1053/j.gastro.2019.05.002

This article is from Murmurs Issue 34 (May – Aug 2019). Click here to read the full issue.