1-Carbon Cycle Metabolites Methylate Their Way to Fatty Liver

Abstract

Fatty liver is a complex disease often accompanying metabolic syndrome and Type 2 diabetes mellitus (T2DM). Hepatosteatosis may have roots in multiple metabolic abnormalities. However, metabolic dysfunction in the 1-carbon cycle (1CC), which produces the methyl donor S-adenosylmethionine (SAM) and phosphatidylcholine (PC), induces hepatic lipogenesis in model systems. Human diseases where 1CC or PC synthesis is disrupted, such as alcoholism, congenital lipodystrophy, or cystic fibrosis, often present with fatty liver. Given that the 1CC is clearly linked to this disease, it is critical to understand how the individual metabolites drive mechanisms increasing stored hepatic lipids. In this review, I summarize evidence that ties the 1CC to fatty liver disease along with data proposing mechanisms for increased lipogenesis or decreased lipid export by phosphatidylcholine.

Keywords: 1-carbon cycle; fatty liver; methylation; phosphatidylcholine.

Figure 1. Schematic diagram of the 1CC

The 1-carbon cycle (1CC) consists of multiple interlocking pathways. Folate enters the cycle leading to MTFH (methyl tetrahydrofolate) conversion to methionine by MS (methionine synthase). Methionine is used to make SAM, which can be used by MTs to produce methylated proteins (including histones), nucleic acids, phosphatidylcholine (PC) or metabolites such as Sarcosine (Sar). The byproduct of these reactions, s-adenosylhomocysteine (SAH), can be used to regenerate methionine. Homocysteine (HCY), which is produced during the reconversion process, can also be diverted to Glutathione (GSH) production. Enzymes discussed in the text are in green, key metabolites in red. Enzymes: MTHFR (methyl tetrahydrofolate reductase), MS (methionine synthase), MAT (Methionine adenosyl transferase), BHMT (betaine hydroxy methyltransferase), GMNT (glycine n-methyltransferase), PEMT (phosphatidylethanolamine methyltransferase), PCYT1 (phosphocholine cytididyl transferase). Metabolites: THF (tetra-hydrofolate), MTHF (methyl tetra-hydrofolate), HCY (homocysteine), Met (methionine), GSH (glutathione), SAM (s-adosylmethionine), SAH (s-adenosyl homocysteine), PE (phosphatidylethanolamine), Gly (Glycine), Sar (Sarcosine), 2-MG (2-methyl glycine), MT (methyltransferase).

Figure 2: (Key Figure). Diagram illustrating pathways affected by low SAM or low PC that could lead to fatty liver

The 1CC (1-carbon cycle) has multiple links to lipid accumulation in the liver. SAM, the major methyl donor, can potentially directly affect gene expression if histone or DNA methylation patterns are sensitive to SAM levels. Furthermore, through changes phosphatidylcholine (PC) levels, activation of SREBP-1-dependent genes for lipogenesis or LHR-1 dependent genes for bile export could impact lipid accumulation in the liver. Finally, lower levels of PC could also limit export of lipoprotein particles, increasing total hepatic lipid levels. 1CC (1-Carbon Cycle), PC (phosphatidylcholine), LHR-1 (Liver homology receptor 1) SREBP-1 (sterol regulatory element binding protein -1), VLDL (very low density lipoprotein), LHR-1 (liver receptor homolog 1).