patatin like phospholipase domain containing 3
The PNPLA3 gene provides instructions for making a protein called adiponutrin, which is found in fat cells (adipocytes) and liver cells (hepatocytes). The liver is a part of the digestive system that helps break down food, store energy, and remove waste products, including toxins. The function of the adiponutrin protein is not well understood, but it is thought to help regulate the development of adipocytes and the production and breakdown of fats (lipogenesis and lipolysis) in hepatocytes and adipocytes. Studies indicate that the activity (expression) of the PNPLA3 gene decreases during periods without food (fasting) and increases after eating, suggesting that the amount of adiponutrin protein produced is regulated as needed to help process and store fats in the diet.
A particular variation in the PNPLA3 gene has been associated with an increased risk of developing non-alcoholic fatty liver disease (NAFLD). NAFLD is a buildup of excessive fat in the liver that can lead to liver damage resembling the damage caused by alcohol abuse, but that occurs in people who do not drink heavily. In some cases NAFLD leads to inflammation of the liver (non-alcoholic steatohepatitis, also known as NASH) and permanent liver damage (cirrhosis).
The PNPLA3 gene variation associated with NAFLD changes the protein building block (amino acid) isoleucine to the amino acid methionine at protein position 148, written as Ile148Met or I148M. Research suggests that the altered protein leads to increased production and decreased breakdown of fats in the liver. Studies are ongoing to determine how this and other genetic changes contribute to the development of NAFLD and its complications.
The I148M variation of the PNPLA3 gene has also been associated with the worsening of other liver diseases, such as a viral infection called hepatitis C. The variation also increases the risk of liver damage in people with alcoholism. The mechanism of this effect is not well understood, but the altered protein appears to increase fibrosis of the liver in people with these conditions.
This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/gene/pnpla3