Choline metabolism provides novel insights into nonalcoholic fatty liver disease and its progression

Abstract

Purpose of review: Choline is an essential nutrient and the liver is a central organ responsible for choline metabolism. Hepatosteatosis and liver cell death occur when humans are deprived of choline. In the last few years, there have been significant advances in our understanding of the mechanisms that influence choline requirements in humans and in our understanding of choline's effects on liver function. These advances are useful in elucidating why nonalcoholic fatty liver disease (NAFLD) occurs and progresses sometimes to hepatocarcinogenesis.

Recent findings: Humans eating low-choline diets develop fatty liver and liver damage. This dietary requirement for choline is modulated by estrogen and by single-nucleotide polymorphisms in specific genes of choline and folate metabolism. The spectrum of choline's effects on liver range from steatosis to development of hepatocarcinomas, and several mechanisms for these effects have been identified. They include abnormal phospholipid synthesis, defects in lipoprotein secretion, oxidative damage caused by mitochondrial dysfunction, and endoplasmic reticulum stress. Furthermore, the hepatic steatosis phenotype can be characterized more fully via metabolomic signatures and is influenced by the gut microbiome. Importantly, the intricate connection between liver function, one-carbon metabolism, and energy metabolism is just beginning to be elucidated.

Summary: Choline influences liver function, and the dietary requirement for this nutrient varies depending on an individual's genotype and estrogen status. Understanding these individual differences is important for gastroenterologists seeking to understand why some individuals develop NAFLD and others do not, and why some patients tolerate total parenteral nutrition and others develop liver dysfunction.

Figure 1. Choline, folate and homocysteine metabolism are closely interrelated

The pathways for the metabolism of these three nutrients intersect at the formation of methionine from homocysteine. BADH=betaine aldehyde dehydrogenase; BHMT=betaine homocysteine methyltransferase; ChAT=choline acetyltransferase; CHDH=choline dehydrogenase; CK=choline kinase; CPT=choline phosphotransferase; CT=CTP:phosphocholine cytidylytransferase; MS=methionine synthase; mTHF=methyl tetrahydrofolate PEMT=phosphatidylethanolamine-N-methyltransferase; THF=tetrahydrofolate From: Present Knowledge in Nutrition Volume 10, with permission.

Figure 2. Summary of Choline Deficiency Mediated Mechanisms of Liver Dysfunction

The progression of NAFLD from simple steatosis to hepatocarcinoma is influenced by multiple cholinemediated mechanisms.