B Vitamins May Be Inexpensive Treatment for Advanced Non-Alcoholic Fatty Liver Disease



Researchers from Singapore discover a direct relationship between hyperhomocysteinemia and the severity of non-alcoholic steatohepatitis.

Researchers from Duke-NUS Medical School in Singapore have shown a high correlation between the severity of an advanced form of non-alcoholic fatty liver disease and elevated blood levels of the amino acid homocysteine.

They also discovered that vitamin B12 and folic acid (vitamin B9) could be utilized to stop or slow the progression of disease.

Scientists at Duke-NUS Medical School in Singapore have discovered a mechanism that causes a severe form of fatty liver disease. It turns out that taking doses of folic acid and vitamin B12 could stop this process.

These discoveries may be beneficial to those who suffer from non-alcoholic fatty liver disease, a catch-all phrase for a variety of liver diseases that affect people who consume little to no alcohol. Four out of ten persons in Singapore and 25% of all adults worldwide are affected by this common ailment.

Our research is significant and interesting because it suggests that vitamin B12 and folic acid, two relatively cheap treatments, may be utilized to stop or slow the development of NASH. — Brijesh Singh, M.D.

The most common reason for liver transplants worldwide is non-alcoholic fatty liver disease, which causes fat to accumulate in the liver. Due to its link to diabetes and obesity, two serious public health issues in Singapore and other developed countries, it has a high prevalence. Non-alcoholic steatohepatitis is the term used when the disorder proceeds to inflammation and the production of scar tissue (NASH).

While liver fat deposition can be reversed in its early stages, the development of NASH leads to liver dysfunction, cirrhosis, and an increased risk of liver cancer, according to Dr. Madhulika Tripathi, the study's first author and a senior research fellow in the Cardiovascular & Metabolic Program at Duke-NUS.

There are presently no pharmacological treatments available for NASH since researchers don't fully comprehend how the condition works. Although elevated blood levels of the amino acid homocysteine are known to be connected with NASH, it is unknown whether or not this amino acid contributes to the disorder's development.

How B vitamins may help those with non-alcoholic fatty liver disease treat or prevent non-alcoholic steatohepatitis

The researchers discovered that hyperhomocysteinemia, a medical condition marked by elevated serum and hepatic homocysteine levels, is directly correlated with the severity of non-alcoholic steatohepatitis (NASH) in people with non-alcoholic fatty liver disease that has advanced to NASH. Western-style diets, which are typically high in fructose intake, can cause this. They showed that hyperhomocysteinemia results in homocysteinylation of the essential autophagy protein STX17, which inhibits autophagy during the onset and development of NASH. In addition to restoring autophagy, which is a crucial biological process by which cells eliminate misfolded proteins or damaged organelles, vitamin B12 and folate supplementation significantly decreased overall NASH pathology. Photo courtesy of Duke-NUS Medical School

The relationship between homocysteine and the development of NASH in preclinical models and people was validated by Dr. Tripathi, research co-author Dr. Brijesh Singh, and their associates in Singapore, India, China, and the US. They also found that homocysteine linked to several liver proteins, altering their structure and preventing proper function, as the liver's homocysteine levels rose. Homocysteine specifically prevented a protein known as syntaxin 17 from carrying and digesting fat (known as autophagy, an important cellular process by which cells eliminate misfolded proteins or damaged organelles) in fatty acid metabolism, mitochondrial turnover, and the suppression of inflammation. This caused NASH to develop and progress from fatty liver disease.

Professor Paul M. Yen, the study's senior author, and lead authors Senior Research Fellow Dr. Madhulika Tripathi and Assistant Professor Brijesh Kumar Singh oversaw the Duke-NUS Medical School research team. Photo courtesy of Duke-NUS Medical School

Importantly, the researchers discovered that adding vitamin B12 and folic acid to the preclinical models' diets raised the levels of syntaxin 17 in the liver and restored its function in autophagy. Additionally, it stopped the progression of NASH and treated liver fibrosis and inflammation.

Because they imply that a reasonably cheap medication, vitamin B12 and folic acid, could be used to stop or delay the advancement of NASH, Dr. Singh noted that his team's findings are both fascinating and significant. Homocysteine levels in the liver and serum could also be used as a biomarker to gauge the severity of NASH.

Finding out whether liver proteins may also be impacted similarly by homocysteine is one of the team's future research priorities. They anticipate that additional study will result in the creation of anti-NASH treatments.

"The potential for using vitamin B12 and folate, which have high safety profiles and are classified as dietary supplements by the US Food and Drug Administration, as first-line therapies for the prevention and treatment of NASH could result in tremendous cost savings and reduce the health burden from NASH in the population," said Professor Paul M. Yen, Head of the Laboratory of Hormonal Regulation at Duke-NUS' Cardiovascular & Metabolic Disorders Program and senior author of the study.

Professor Patrick Casey, Senior Vice-Dean for Research at Duke-NUS, stated that a liver transplant is currently the sole option for patients with end-stage liver disease. Dr. Tripathi and her colleagues' research shows that a straightforward, reasonably priced, and easily accessible intervention may be able to prevent or reverse liver damage, giving patients who have fatty liver illnesses fresh hope. The team's findings highlight the importance of basic scientific research, which enables the scientific community to continue having a significant positive impact on patients' lives.

By reducing Syntaxin 17 homocysteinylation, vitamins B12 and folate reduce inflammation and fibrosis in NASH, according to research by Madhulika Tripathi, Brijesh Kumar Singh, Jin Zhou, Keziah Tikno, Anissa Widjaja, Reddemma Sandireddy, Kabilesh Arul, and Siti Aishah. Ayako Suzuki, Teegan Reina Lim, Chang-Chuen Cheah, Jue Wang, Rui-Ping Xiao, Xiuqing Zhang, Pierce Kah Hoe Chow, and Paul Michael Yen, 8 July 2022, Journal of Hepatology. Binte Abdul Ghani, George Goh Boon Bee, Kiraely Adam Wong, Ho Jia Pei, Shamini Guna Shekeran, Rohit Anthony Sinha, Manv

By DUKE-NUS MEDICAL SCHOOL

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