Impact Of Choline in Patients With NAFLD

Non-alcoholic fatty liver disease (NAFLD) has attracted increasing attention given its high prevalence, estimated at 20% to 44% in Western countries and 5% to 38% in Asia as well as its correlation with cardiovascular morbidity and mortality.

NAFLD is the result of hepatic fat accumulation in patients without a history of excessive alcohol consumption, predisposing medications or other defined liver disorders. NAFLD comprises a spectrum of liver disorders. At one end of this spectrum, is simple hepatic steatosis and the other end is non-alcoholic steatohepatitis (NASH) which is characterized by hepatocellular injury, inflammation and fibrosis sometimes leading to cirrhosis. It is considered the hepatic manifestation of metabolic syndrome, which is defined by the presence of central obesity, insulin resistance, hyperlipidemia, hyperglycemia, and hypertension.

According to the multiple parallel hits in NAFLD pathogenesis, the first hit is insulin resistance, which results in increased hepatic de novo lipogenesis and impaired adipose tissue lipolysis.These conditions cause an efflux of free fatty acids from the adipose tissue to the liver. The liver becomes vulnerable to a series of hits, including oxidative stress and dysregulation of adipokines such as leptin.

It has been also observed that fatty liver can occur both in people with a normal body mass index (BMI) (10-24% of the population has fatty liver) and in 95% of adults with obesity.

Choline is an essential nutrient for human health, which exerts various physiological functions:

1. It is acetylated to generate acetylcholine, the important neurotransmitter;
2. It is oxidized to pass methyl to S-adenosylmethionine, a universal methyl group donor, which participates in the methylation-dependent biosynthesis of DNA, RNA and protein;
3. It is phosphorylated to synthesize phosphatidylcholine, a major constituent of cell and mitochondrial membranes, which is involved in the mitochondrial bioenergetics regulating lipid and glucose metabolism. In addition, it takes part in the packaging and exporting of triglyceride (TG) in very low-density lipoprotein (VLDL), as well as the solubilizing of bile salts for secretion.

Choline deficiency contributes to various disorders in animals and humans, with liver as its main target. Humans deprived of choline have been perceived to develop fatty liver, liver cell death or skeletal muscle damage, which were further proven by another clinical study revealing that patients fed with total parenteral nutrition (TPN) solutions low in choline resulted in TPN-associated liver disease.

Growing evidence has suggested certain effects of choline on mitochondrial metabolism. Low choline results in the altered composition of mitochondrial membranes, reduced mitochondrial membrane potential, decreased Adenosine triphosphate production and disturbance in fatty acid β-oxidation in rats fed a choline-deficient diet. This mitochondrial dysfunction has also been linked to the process of the increase of reactive oxygen species (ROS) generation, the loss of mitochondrial membrane potential, cellular apoptosis and hepatocarcinogenesis caused by choline deficiency in rat hepatocytes. However, the specific mechanisms connecting choline, DNA methylation and metabolic diseases, such as non-alcoholic fatty liver disease (NAFLD), remain to be evidently described.

Excessive energy substrates available to the hepatocytes can potentially result in cellular steatosis with the increasing generation of free fatty acids (FFA) and ROS, which, in turn, will lead to mitochondrial dysfunction inseparably linked with oxidative stress. This is fundamental to the development of dietary-induced NAFLD or TPN-associated liver disease under unbalanced nutrients distress and can potentially lead to steatohepatitis, fibrosis and cirrhosis in the liver.

Considering those mechanisms, hence it is interesting to study whether supplementation of choline could have a potential benefit in NAFLD patients. Choline has been shown to decrease lipoprotein oxidation, generation of inflammatory mediators and reactive oxygen species, maintain lipid and glucose homeostasis and help in the repair of mitochondrial membrane.

Patients with NAFLD exhibit increased levels of hepatic cytochrome P450-2E1 and thiobarbituric acid reactants, which are markers of lipid peroxidation. Oxidative stress has been demonstrated in animal and human studies to be a significant factor, responsible for causing progression of NAFLD to NASH. In this respect, it may be regarded as an important second hit.

Oxidative stress in fatty liver arises because of excessive fatty acid oxidation resulting in an increase release of reactive oxygen species. Another study demonstrated that, total lipid peroxidation products as represented by TBARS were significantly higher among patients with NAFLD as compared to patients with either chronic viral hepatitis or healthy controls.

This suggests that the occurrence of high plasma concentration of products of lipid peroxidation is a unique phenomenon in patients with NAFLD and not only a byproduct of any inflammation, because TBARS was lower among patients with chronic viral hepatitis who had high degree of necroinflammation.

Leptin, an important regulatory energy hormone, is released from adipocytes and may play a role in the development of liver steatosis. High levels of serum leptin have been reported in patients with NAFLD.

Although the underlying mechanisms of leptin in NAFLD are incompletely understood, it has been suggested that it affects fat deposition, fibrogenesis, and inflammation in the liver of patients with NAFLD.

In NAFLD, the dysregulation of adipokines, including leptin, mediate insulin resistance through reduced insulin signaling, increased fatty acid concentrations in the liver, and promote steatosis.In addition to hyperinsulinemia, a feature of insulin resistance is the stimulatory effect on the leptin gene, which causes the release of leptin in a vicious cycle.