High-fat diet consumption reduces hepatic folate transporter expression via nuclear respiratory factor-1
Citation
Sid, V., Siow, Y.L., Shang, Y., Woo, C.W., Karmin, O. (2018). High-fat diet consumption reduces hepatic folate transporter expression via nuclear respiratory factor-1. Journal of Molecular Medicine, [online] 96(11), 1203-1213. http://dx.doi.org/10.1007/s00109-018-1688-8
Plain language summary
Folate or vitamin B9 is one of the essential micronutrient for many biological functions involving protein metabolism and DNA synthesis. Foods that are high in folate include dark leafy vegetables (such as brussel sprouts, kale, lettuce and spinach) and legumes (such as beans, green peas, and lentils). Despite adequate consumption of folate from diets and supplements, obese individuals, patients with non-alcoholic fatty liver disease and subsets of senior population have low folate levels. In this study using a diet-induced mouse model of obesity, researchers found that low levels of folate in serum and liver were associated with decreased levels of key folate transporters in liver. These transporters help maintain adequate levels of folate in the body. Further investigative analyses demonstrate that low level of the protein that turns on genes for the folate transporters was responsible for the defect. The results of the study solve the puzzling question for physicians and dietitians of why obese patients and others have low folate levels despite adequate intake. Due to increased global prevalence of obesity, folate deficiency is expected to rise with most impacts on both women in childbearing age and aging population.
Abstract
Abstract: Folate is an essential micronutrient for biological function. The liver, a primary organ for folate metabolism and storage, plays an important role in folate homeostasis. Proton-coupled folate transporter (PCFT) and reduced folate carrier (RFC) are the major folate transporters responsible for folate uptake at basolateral membrane of hepatocytes. Low serum folate levels are frequently associated with obesity. We investigated the mechanism that regulated folate status in a mouse model with diet-induced obesity. Mice (C57BL/6J) were fed a high-fat diet (60% kcal fat) for 8 weeks. Mice displayed increased hepatic lipid accumulation and decreased folate levels in the liver and serum compared to mice fed a normal chow diet (10% kcal fat). High-fat diet-fed mice had low expression of PCFT and RFC and decreased nuclear respiratory factor-1 (NRF-1)/DNA-binding activity. Treatment with NRF-1 siRNA or palmitic acid reduced folate transporter expression in hepatocytes. Inhibition of NRF-1 mediated folate transporter expression significantly reduced intracellular folate levels. These results suggest that chronic consumption of high-fat diets impairs folate transporter expression via NRF-1-dependent mechanism, leading to reduced hepatic folate storage. Understanding the regulation of folate homeostasis in obesity may have an important implication in current guideline of folate intake. Key messages: Serum and liver folate levels are decreased in diet-induced obese mice.Chronic high-fat diet consumption impairs expression of hepatic PCFT and RFC.NRF-1 regulates hepatic folate transporters expression and folate levels.