B vitamins may be an inexpensive treatment for advanced non-alcoholic fatty liver disease

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Scientists from Singapore found that hyperhomocysteinemia was strongly correlated with the severity of non-alcoholic steatohepatitis.

  • Scientists from Duke-NUS Medical School in Singapore have found that elevated blood levels of the amino acid acid called homocysteine ​​are strongly correlated with the severity of an advanced form of non-alcoholic fatty liver disease.
  • They also discovered that vitamin B12 and folic acid (vitamin B9) could be used to prevent and/or delay disease progression.

A mechanism that leads to an advanced form of fatty liver has been discovered by scientists at Duke-NUS Medical School in Singapore. It turns out that vitamin B12 and folic acid supplements could reverse this process.

These findings could help people with non-alcoholic fatty liver disease, an umbrella term for a range of liver conditions affecting people who drink little or no alcohol. It is a widespread condition that affects 25% of all adults worldwide and four in 10 adults in Singapore.

“Our findings are both exciting and important because they suggest that a relatively inexpensive therapy, vitamin B12 and folic acid, could be used to prevent and/or delay the progression of NASH.” — Dr Brijesh Singh

Non-alcoholic fatty liver disease involves fatty buildup in the liver and is one of the leading causes of liver transplants worldwide. Its high prevalence is due to its association with diabetes and obesity, two major public health problems in Singapore and other industrialized countries. When the disease progresses to inflammation and the formation of scar tissue, it is called non-alcoholic steatohepatitis (NASH).

“While fat deposition in the liver is reversible in its early stages, its progression to NASH causes liver dysfunction, cirrhosis and increases the risk of liver cancer,” said Dr. Madhulika Tripathi, first author of the study, who is principal investigator. with the Hormone Regulation Laboratory of the Duke-NUS Cardiovascular and Metabolic Program.

Because scientists do not understand the mechanisms of NASH, there is currently no pharmacological treatment for the disease. Although researchers know that NASH is associated with high blood levels of an amino acid called homocysteine, they were unsure what role, if any, it plays in the development of the disease.

How B vitamins could potentially treat or prevent nonalcoholic steatohepatitis in people with nonalcoholic fatty liver disease

Western-style diets, which are typically high in fructose, can lead to high levels of serum and liver homocysteine ​​in the blood (a medical condition known as hyperhomocysteinemia), which the research team found to be directly proportional to the severity of non-alcoholic steatohepatitis (NASH) in people with non-alcoholic fatty liver disease that progressed to NASH. They demonstrated that hyperhomocysteinemia causes homocysteinylation of the key autophagy protein STX17, resulting in autophagy inhibition during the development and progression of NASH. Vitamin B12 and folate supplementation not only restored autophagy (an essential cellular process by which cells eliminate malformed proteins or damaged organelles), but it also reduced the overall pathology of NASH. Credit: Duke-NUS School of Medicine

Dr. Tripathi, study co-author Dr. Brijesh Singh, and their colleagues in Singapore, India, China, and the United States confirmed the association of homocysteine ​​with NASH progression in preclinical models and in humans. They also found that as homocysteine ​​levels increased in the liver, the amino acid attached to various liver proteins, changing their structure and impairing their function. Specifically, when homocysteine ​​is attached to a protein called syntaxin 17, it prevents the protein from performing its role of transporting and digesting fat (known as autophagy, an essential cellular process by which cells eliminate fats). malformed proteins or damaged organelles) in fatty acid metabolism, mitochondrial turnover and prevention of inflammation. This induced the development and progression of fatty liver to NASH.

Paul Yen, Madhulika Tripathi and Brijesh Kumar Singh

The Duke-NUS Medical School research team was led by Professor Paul M. Yen, lead author of the study, and lead authors Dr. Madhulika Tripathi and Assistant Professor Brijesh Kumar Singh. Credit: Duke-NUS School of Medicine

Importantly, scientists found that supplementing the diet in preclinical models with vitamin B12 and folic acid increased levels of syntaxin 17 in the liver and restored its role in autophagy. It also slowed the progression of NASH and reversed liver inflammation and fibrosis.

“Our findings are both exciting and important because they suggest that a relatively inexpensive therapy, vitamin B12 and folic acid, could be used to prevent and/or delay the progression of NASH,” said Dr. Singh. “Additionally, serum and liver homocysteine ​​levels could serve as a biomarker of NASH severity.”

Homocysteine ​​may similarly affect other liver proteins, and finding out what they are is a future research direction for the team. They hope that further research will lead to the development of anti-NASH therapies.

Professor Paul M. Yen, head of the Hormone Regulation Laboratory in the Cardiovascular and Metabolic Disorders Program at Duke-NUS and lead author of the study, said: “The potential for use of vitamin B12 and folate, which have high safety profiles and are designated as dietary supplements by the United States Food and Drug Administration, as first-line therapies for the prevention and treatment of NASH, could result in huge cost savings and reduce the health burden of NASH in developed and developing countries.

Professor Patrick Casey, Senior Associate Dean for Research at Duke-NUS, said: “Currently the only treatment for patients with end-stage liver disease is to receive a transplant. The findings of Dr. Tripathi and his colleagues demonstrate that a simple, affordable and accessible intervention could potentially halt or reverse liver damage, bringing new hope to people with fatty liver disease. The team’s findings underscore the value of basic scientific research, through which the scientific community continues to have a major positive impact on the lives of patients.

The research was published in the Journal of Hepatology.

Reference: “Vitamin B12 and folate decreases inflammation and fibrosis in NASH by preventing homocysteinylation of syntaxin 17” by Madhulika Tripathi, Brijesh Kumar Singh, Jin Zhou, Keziah Tikno, Anissa Widjaja, Reddemma Sandireddy, Kabilesh Arul, Siti Aishah Binte Abdul Ghani, George Goh Boon Bee, Kiraely Adam Wong, Ho Jia Pei, Shamini Guna Shekeran, Rohit Anthony Sinha, Manvendra K. Singh, Stuart Alexander Cook, Ayako Suzuki, Teegan Reina Lim, Chang-Chuen Cheah, Jue Wang, Rui-Ping Xiao, Xiuqing Zhang, Pierce Kah Hoe Chow and Paul Michael Yen, July 8, 2022, Journal of Hepatology.
DOI: 10.1016/j.jhep.2022.06.033

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