Non-alcoholic fatty liver disease (NALFD) is the most common chronic liver disease and is characterized by the accumulation of lipids in the liver independent of alcohol use. 

The Liver's Role in Fatty Acid Metabolism

The liver is not a major storage center for fatty acids and triglycerides but following periods of feeding or fasting there is movement of fats into and out of the liver.  Following digestion of food in the stomach, fats are absorbed from the small intestine and assembled into triglycerides. 

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Figure 1. Kawano and Cohen (2013)

Triglycerides are incorporated into chylomicrons which deliver about 70% of all fats to adipose tissue with the rest going to the liver (1).  Additionally, when there is an abundance of carbohydrates, fatty acids will be  synthesized by the liver and which can be incorporated into lipoproteins and released (2).  However, under fasting conditions fatty acids released from adipose tissue are taken up by the liver and used to synthesize triglycerides which are then incorporated into lipoproteins and released into the blood.  Fatty acids taken up by the liver can also be oxidized and used in gluconeogenesis (3).  In both cases the level of fat in the liver is highly regulated.  Figure 1  illustrates the numerous ways in which fat levels are regulated in the liver. However in NALFD triglycerides accumulate in hepatocytes which leads to liver dysfunction. 

NALFD and the Renin-Angiotensin System

The renin-angiotensin system (RAS) plays an important role in regulating blood pressure and maintaining  cardiovascular homeostasis (4) and is expressed in a variety of tissues including the liver.  Over activation of RAS has been seen in patients with cirrhosis (5) and chronic hepatitis C (6) while inhibition of RAS in animal models decreases hepatic fibrogenisis in animal models (7). A study using mice that had high tissue levels of angiotensin II developed steatohepatitis and hepatic fibrosis (8). Activation of angiotensin II type 1 receptor results in the expression of TGFβ-1, a profibrogenetic cytokine, in response to liver injury(9).  While animal studies have reveled that deletion of this receptor reduces the occurrence of fat accumulation in the liver (10).  These studies suggest that activation of this receptor can result in the development of NALFD.  Thus mutations that alter the functioning of this receptor could lead to NALFD. 

Mutations to Angiotensin II type 1 receptor and the Chance of Developing NAFLD

A study of 16 single nucleotide polymorphisms (SNPs) to the angiotensin II type 1 receptor found a strong correlation with NALFD and 5 of the mutations in Japanese patients (11).  However a more recent study did not find a correlation between the five mutations but did find a correlation between fibrosis and different polymorphism in Indian patents (12).  This study was done using Indian, Chinese, and Malaysian patients compared to the Japanese patients used in the initial study. The differences in susceptibility to NALFD seen in these two studies may be due to population differences (11).  Thus susceptibility seems to depend on an individuals ethnic background.  So a person of Northern European decent who has one of the polymorphism that was linked to NALFD in a Japanese person may not have the same susceptibility due to other biological factors.  Dr.  Burke does not have any of the mutations identified in these studies so is not at an increased risk of developing NALFD based on these results.  However, as yet unidentified mutations may influecnce the chance of developing NALFD. 


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