NASH: non alcoholic steatohepatitis, a form of “NAFLD” or nonalcoholic fatty liver disease is characterized by the accumulation of fat in the liver. It is the most common liver disease in the world. It affects more than 90% of obese people, 60% of diabetics and up to 20% of people of normal weight. The liver can “stay fatty” without disruption of its normal function, but this condition can also progress to non-alcoholic steatohepatitis, a more aggressive form of fatty liver disease associated with inflammation and fibrosis, a condition which can in turn progress to cirrhosis then liver cancer and death. Unrelated to alcohol consumption by definition, the first stage of non-alcoholic fatty liver disease is asymptomatic.
“While fat deposition in the liver is reversible in its early stages, progression to NASH causes liver dysfunction, cirrhosis and increases the risk of liver cancer,” recalls lead author Dr. Madhulika Tripathi, researcher in Cardiovascular and Metabolic Medicine at Duke-NUS. Currently, there is no pharmacological treatment for NASH and the mechanisms of the disease remain poorly understood. Although scientists know that NASH is associated with elevated blood levels of an amino acid, homocysteine, they are unaware of its role in the development of the disease.
The team deciphers this mechanism and reveals that a simple vitamin, vitamin B12, could prevent or help treat non-alcoholic steatohepatitis.
Hyperhomocysteinemia correlated with non-alcoholic steatohepatitis (NASH)
The Western diet, which is generally high in fructose, can cause elevated serum and liver levels of homocysteine in the blood, a condition known as hyperhomocysteinemia. The team shows here that:
- hyperhomocysteinemia is directly proportional to the severity of steatohepatitis;
- hyperhomocysteinemia causes homocysteinylation of the key autophagy protein STX17, which induces inhibition of autophagy during the development and progression of NASH;
- Specifically, as homocysteine levels rise in the liver, the amino acid homocysteine attaches to different liver proteins, changing their structure and impairing their function. In particular, when homocysteine is attached to a protein called syntaxin 17, it prevents the protein from performing its role of transporting and digesting fats, as part of the process of autophagy, an essential cellular process by which cells eliminate malformed proteins or damaged organelles, during fatty acid metabolism. This promotes the development and progression of fatty liver disease to NASH.
Vitamin B12 supplementation and folate not only restores autophagy but also reduces the severity of NASH.
The researchers show in preclinical models of fatty liver disease that supplementation with vitamin B12 and folic acid increases levels of syntaxin 17 in the liver and restores autophagy. This supplementation slows the progression of NASH and reverses liver inflammation and fibrosis.
Thus, the study suggests that a relatively inexpensive therapy, vitamin B12 and folic acid supplementation, could prevent and/or delay the progression of NASH. Finally, serum and hepatic homocysteine levels could constitute an excellent biomarker of the severity and evolution of NASH.
Key findings for the millions of people with non-alcoholic fatty liver disease.