Non-alcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver diseases that are characterized by steatosis (hepatic lipid accumulation), inflammation, fibrosis, and liver injury. Chronic consumption of high-fat diets is a major cause of obesity and NAFLD. Because NAFLD is a multifaceted disorder with many underlying metabolic abnormalities, currently, there is no pharmacological agent that is therapeutically approved for the treatment of NAFLD. Folate is a water-soluble B vitamin that has been demonstrated to have antioxidant functions and lipid-lowering effects. The general objective of my research was to investigate the role of folate in the context of high-fat diet-induced NAFLD. A low level of folate in the circulation is often observed in patients with obesity. A low level of endogenous folates in rodents perturbs folate-dependent one-carbon metabolism, and may be associated with development of metabolic diseases such as NAFLD. The first part of my research focused on identifying the underlying mechanisms that are responsible for regulating folate status during high-fat diet feeding. Our results have shown that high-fat diet feeding reduces folate levels in the liver and serum by attenuating expression of hepatic folate transporters in mice. Such effect is mediated through inhibition of nuclear respiratory factor-1 (NRF-1), an important transcriptional regulator of folate transporters. Hepatic lipid and glucose metabolism is frequently perturbed in patients with NAFLD. Similarly, high-fat diet feeding was demonstrated to significantly elevate lipid and glucose levels in the liver of rodents. The second part of my research aimed to investigate the effects of folic acid supplementation on hepatic metabolic regulation in high-fat diet fed mice. Our results have demonstrated that folic acid supplementation effectively lowers hepatic cholesterol and glucose levels in high-fat diet fed mice through activation of AMPK, a master regulator of whole body energy balance and metabolic homeostasis. Activation of AMPK by folic acid was mediated through an elevation of its allosteric activator AMP and phosphorylation of its upstream kinase, namely, liver kinase B1 (LKB1) in the liver.
Hepatic inflammation is an important mediator of NAFLD pathogenesis. The third part of my research aimed to investigate the regulation of hepatic inflammation by folic acid supplementation in high-fat diet fed mice. Our results have shown that folic acid supplementation attenuated the inflammatory response induced by high-fat diet consumption by reducing the expression of inflammatory cytokines (IL-6, TNF-α) in mouse liver. The anti-inflammatory effect of folic acid was mediated via inhibition of NF-κB, a key transcriptional regulator of pro-inflammatory genes. This was associated with decreased deposition of hepatic lipids and inflammatory foci in mice. Taken together, our results have demonstrated that chronic consumption of high-fat diets leads to development of metabolic abnormalities and disrupts folate homeostasis, which results in low folate status in the body. Folic acid supplementation can restore hepatic metabolism and reduce inflammation in high-fat diet fed mice. This suggests that folic acid may have therapeutic implications for the management of NAFLD.