Scientists at Duke-NUS Medical School, Singapore, have found that elevated blood levels of an amino acid called homocysteine correlate strongly with the severity of an advanced form of non-alcoholic fatty liver disease. It was also discovered that vitamin B12 and folic acid could be used to prevent and/or delay disease progression.
Scientists at Duke-NUS Medical School in Singapore have uncovered a mechanism that leads to an advanced form of fatty liver disease, which may potentially be reversed by the supplementation of vitamin B12 and folic acid. 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 to no alcohol, which affects 25 per cent of all adults globally, and four in ten adults in Singapore.
Non-alcoholic fatty liver disease involves fat build-up in the liver and is a leading cause 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 industrialised 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 and senior research fellow with the Laboratory of Hormonal Regulation at Duke-NUS’ Cardiovascular & Metabolic Programme.
Currently, there are no pharmacological treatments for NASH as the mechanisms of the disease remain a mystery to scientists.
Though it is known that NASH is associated with elevated blood levels of a particular amino acid, homocysteine, its exact role in the development of the disorder is not known.
Fortunately, in her study, Dr. Tripathi, together with Dr. Brijesh Singh and their colleagues in Singapore, India, China, and the US, have confirmed the association of homocysteine with NASH progression in preclinical models and humans. They also found that as homocysteine levels increased in the liver, it attaches to various liver proteins, modifying their structure and impeding their functioning.
In particular, when homocysteine attaches to syntaxin 17 (a liver protein), it blocks 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 induces 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 the researchers hope to learn more about their effects on other types of proteins. 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, expressed his hope that the findings by Dr. Tripathi and her colleagues will eventually be a simple, affordable and accessible intervention to slow down, stop or even reverse liver damage, to bring respite to those suffering from fatty liver damage, reduce the progression of the disease to the end stage such that there would be a reduced need for liver transplants.
Source: Duke-NUS Medical School