Researchers discovered that high levels of an amino acid called homocysteine in the blood correspond dramatically with the severity of an advanced form of non-alcoholic fatty liver disease. They also discovered that vitamin B12 and folic acid may be utilised to prevent or postpone illness development.
These findings might benefit persons suffering from non-alcoholic fatty liver disease, a phrase that refers to a group of liver disorders that afflict people who consume little to no alcohol and affects 25% of all adults worldwide and four in ten adults in Singapore. Nonalcoholic fatty liver disease is characterised by fat accumulation in the liver and is the main cause of liver transplants globally.
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 condition progresses to inflammation and scar tissue formation, it is known as 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 for liver cancer,” said Dr Madhulika Tripathi, first author of the study, who is a senior research fellow with the Laboratory of Hormonal Regulation at Duke-NUS’ Cardiovascular & Metabolic Programme.
There are currently no pharmacological therapies for NASH since scientists do not comprehend the disease’s mechanics. Although scientists are aware that NASH is connected with high blood levels of an amino acid called homocysteine, they are unsure what function, if any, it plays in the disorder’s development.
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, changed their structure and impeded their functioning. In particular, when homocysteine is 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.”