Folic Acid Homeostasis and Its Pathways Related to Hepatic Oxidation in Adolescent Rats Exposed to Binge Drinking

Abstract

Chronic ethanol consumption and liver disease are intimately related to folic acid (FA) homeostasis. Despite the fact that FA decreases lipid oxidation, its mechanisms are not yet well elucidated. Lately, adolescents have been practising binge drinking (BD), consisting of the intake of a high amount of alcohol in a short time; this is a particularly pro-oxidant form of consumption. The aim of this study is to examine, for the first time, FA homeostasis in BD adolescent rats and its antioxidant properties in the liver. We used adolescent rats, including control rats and rats exposed to an intermittent intraperitoneal BD model, supplemented with or without FA. Renal FA reabsorption and renal FA deposits were increased in BD rats; hepatic deposits were decreased, and heart and serum levels remained unaffected. This depletion in the liver was accompanied by higher transaminase levels; an imbalance in the antioxidant endogenous enzymatic system; lipid and protein oxidation; a decrease in glutathione (GSH) levels; hyper-homocysteinemia (HHcy); an increase in NADPH oxidase (NOX) 1 and NOX4 enzymes; an increase in caspase 9 and 3; and a decrease in the anti-apoptotic metallopeptidase inhibitor 1. Furthermore, BD exposure increased the expression of uncoupled endothelial nitric oxide synthase (eNOS) by increasing reactive nitrogen species generation and the nitration of tyrosine proteins. When FA was administered, hepatic FA levels returned to normal levels; transaminase and lipid and protein oxidation also decreased. Its antioxidant activity was due, in part, to the modulation of superoxide dismutase activity, GSH synthesis and NOX1, NOX4 and caspase expression. FA reduced HHcy and increased the expression of coupled eNOS by increasing tetrahydrobiopterin expression, avoiding nitrosative stress. In conclusion, FA homeostasis and its antioxidant properties are affected in BD adolescent rats, making it clear that this vitamin plays an important role in the oxidative, nitrosative and apoptotic hepatic damage generated by acute ethanol exposure. For this, FA supplementation becomes a potential BD therapy for adolescents, preventing future acute alcohol-related harms.

Folic acid antioxidant supplementation to binge drinking adolescent rats improves hydric‐saline balance and blood pressure, but fails to increase renal NO availability and glomerular filtration rate

“…The decrease in serum Aldo levels leads to an increase in Na + relative CL, which is indicative of a higher Na + excretion in urine, and consequently an increase in FENa, reducing Na + serum levels. The mechanisms by which FA supplementation partially reduces serum Aldo levels and SBP could be related to its systemic and hepatic antioxidant activity 25,26 . The current study has proven that FA supplementation leads to better urinary excretion of Aldo, which is reflected in a higher Aldo relative CL and lower reabsorption.…”

“…The mechanisms by which FA supplementation partially reduces serum Aldo levels and SBP could be related to its systemic and hepatic antioxidant activity. 25,26 The current study has proven that FA supplementation leads to better urinary excretion of Aldo, which is reflected in a higher Aldo relative CL and lower reabsorption.…”

“…Renal reabsorption of folate is achieved by a high affinity folate receptor (folate receptor 1) that is abundant on the luminal side of proximal tubular epithelial cells 43 ; according to previous data which found that renal FA deposits are repleted in BD-exposed adolescent rats. 25 The FA therapy used in this study seems to be enough since FA relative CL in BD supplemented rats is increased, indicating that FA is secreted into urine. Another important relative CL variation found in BD rats is a decrease in Na + relative CL, coinciding with hypernatremia.…”

“…Among other pathways, FA supplementation could decrease NOX4 expression because, as we have previously measured in the plasma of BD adolescent rats supplemented with FA using the same experimental protocol as in this study, it reduces the Hyper-Hcy found in BD-exposed rats. 25 It is described that Hyper-Hcy leads to an increase in endothelial and kidney NOX4, related to an increase in the ERK1/2/NOX4/ROS/apoptotic pathway and hypertension generation. 41,42 Importantly, while folate is distributed in all cellular compartments, mitochondria can take up to 40% of the folate pool, being FA a selective antioxidant for mitochondrial health and apoptosis. )…”

Adipose tissue homeostasis orchestrates the oxidative, energetic, metabolic and endocrine disruption induced by binge drinking in adolescent rats

“…Finally, the oxidative imbalance also affects energy sensors such as SIRT‐1 and AMPK, which lead cells to catabolism and energy supply. In WAT, it has been confirmed that ROS can induce the activation of AMPK even without changes in the cellular ATP present (Gallego‐Lopez et al., 2022; Quintero et al., 2006; Wu et al., 2012). Relative to SIRT‐1, OS in WAT is also inversely related to SIRT‐1 expression (Manna et al., 2017).…”