Folate, alcohol, and liver disease

Abstract

Alcoholic liver disease (ALD) is typically associated with folate deficiency, which is the result of reduced dietary folate intake, intestinal malabsorption, reduced liver uptake and storage, and increased urinary folate excretion. Folate deficiency favors the progression of liver disease through mechanisms that include its effects on methionine metabolism with consequences for DNA synthesis and stability and the epigenetic regulation of gene expression involved in pathways of liver injury. This paper reviews the pathogenesis of ALD with particular focus on ethanol-induced alterations in methionine metabolism, which may act in synergy with folate deficiency to decrease antioxidant defense as well as DNA stability while regulating epigenetic mechanisms of relevant gene expressions. We also review the current evidence available on potential treatments of ALD based on correcting abnormalities in methionine metabolism and the methylation regulation of relevant gene expressions.

Figure 1. Folate homeostasis

Dietary folate is predominantly in the form of pteroylpolyglutamate (PteGlun) which is then hydrolyzed on the jejunal (J) brush border by a specific gamma carboxy peptidase (1) to yield pteroymonoglutamyl folate (PteGlu) that is methylated and then transported across enterocyte membranes by the reduced folate carrier (2) to the portal vein. Subsequent transport across membranes of hepatocytes in the liver (L) is facilitated by the reduced folate carrier (2), possibly together with folate binding protein or the proton coupled folate transporter. Within the liver, PteGlu is re-polyglutamated by an intracellular folylpolyglutamatesythetase (3) to PteGlun for storage, then released back to PteGlu by a separate gamma glutamyl hydrolase (4) and transported to both the enterohepatic folate circulation (EHFC) or systemic folate circulation (SFC) for transport to all cells of the body. Urinary excretion is regulated in the kidney (K) through re-absorption of about 90% by the reduced folate carrier on renal tubular cells (2). While less than 1 % of folate excreted in stool from the EHFC, about 10% of the SFC pool is excreted daily by the kidney, requiring replacement by dietary folate.

Figure 2. Normal folate and methionine metabolism

After passage through intestine to the liver, dietary folate is metabolized to dihydrofolate (DHF) and then tetrahydrofolate (THF), which is substrate for production of 5,10-methylene tetrahydrofolate (5,10-MTHF). This compound then interacts either with thymidine synthetase (TS) for regulation of nucleotide metabolism in DNA synthesis, or with methyltetrahydrofolate reductase (MHFR), for production of 5-methyltetrahydrofolate (5-MTHF), which is the initial methyl donor for methionine metabolism. Homocysteine and 5-MTHF are substrates for vitamin B12 dependent methionine synthase (MS) for production of methionine and THF. In the transmethylation cycle, methionine is substrate for methionine adenosyl transferase (MAT) to produce S-adenosylmethionine (SAM), which is the principal methyl donor for all histone and DNA methyltransferases (MTsS-adenosylhomocysteine (SAH) is the both product and inhibitor of all MT reactions, and is subsequently metabolized to homocysteine by the bidirectional enzyme SAH hydrolase (SAHH). Through the transsulfuration pathway, homocysteine is metabolized by vitamin B6 regulated pathways, cystathionine beta synthase (CβS) and cystathionase to cysteine and subsequently to the antioxidant glutathione (GSH). In addition to its role as principal methyl donor, SAM regulates both folate metabolism as an inhibitor of MTHFR and transsulfuration of homocysteine as a facilitator of CβS.