B vitamins can potentially be used to treat advanced non-alcoholic fatty liver disease

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

Importantly, the researchers found that supplementing the diet in the preclinical models with vitamin B12 and folic acid increased the levels of syntaxin 17 in the liver and restored its role in autophagy. It also slowed NASH progression 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 hepatic homocysteine levels could serve as a biomarker for 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 Laboratory of Hormonal Regulation at Duke-NUS’ Cardiovascular & Metabolic Disorders Programme, and senior author of the study, said, “The potential for using vitamin B12 and folate, which have high safety profiles and are designated 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 both developed and developing countries.”

Professor Patrick Casey, Senior Vice-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 by Dr Tripathi and her colleagues demonstrate that a simple, affordable and accessible intervention could potentially halt or reverse the damage to the liver, bringing new hope to those suffering from fatty liver diseases. 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.

A CVMD research team has found that elevated blood levels of an amino acid called homocysteine tracks with the severity of an advance form of non-alcoholic fatty liver disease, known as non-alcoholic steatohepatitis (NASH). They also found that vitamin B12 and folic acid supplements slowed NASH progression and reversed liver inflammation and fibrosis in a preclinical model. Pictured from left: Professor Paul M. Yen, senior author of the study, and lead authors Senior Research Fellow Dr Madhulika Tripathi and Assistant Professor Brijesh Kumar Singh.

Western-style diets, which are typically high in fructose intake, can lead to elevated serum and hepatic homocysteine levels in 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 has progressed to NASH. They demonstrated that hyperhomocysteinemia causes homocysteinylation of the key autophagy protein STX17, leading to autophagy inhibition during NASH development and progression. Supplementation with vitamin B₁₂ and folate not only restored autophagy (an essential cellular process by which cells remove malformed proteins or damaged organelles), it also reduced overall NASH pathology. (Credit: Duke-NUS Medical School)