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PNPLA3 gene
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Gene

PNPLA3 gene

The PNPLA3 gene provides instructions for an enzyme that regulates fat metabolism in liver and fat cells.

Normal Function

The PNPLA3 gene provides instructions for making an enzyme that is found in fat cells (adipocytes) and liver cells (hepatocytes). The liver is part of the digestive system, and it helps break down food, store energy, and remove waste products. The PNPLA3 enzyme is thought to help regulate the development of adipocytes and the production and breakdown of fats (lipogenesis and lipolysis) in adipocytes and hepatocytes. Studies indicate that the activity (expression) of the PNPLA3 gene decreases during periods without food (fasting) and increases after eating, suggesting that the PNPLA3 enzyme is produced as needed to help store or break down fats in the liver.

Health Conditions Related to Genetic Changes

Metabolic dysfunction-associated steatotic liver disease

A particular change in the PNPLA3 gene has been associated with an increased risk of developing a condition called metabolic dysfunction-associated steatotic liver disease (MASLD). Genetic changes that increase the risk of disease are called pathogenic variants. In people with MASLD, fat can build up in the liver and cause liver damage.

The PNPLA3 gene variant that is associated with MASLD leads to the substitution of the protein building block (amino acid) isoleucine for the amino acid methionine at protein position 148, written as Ile148Met or I148M. Research suggests that the altered enzyme has decreased activity, resulting in a buildup of fats in the liver. Having this altered PNPLA3 enzyme also increases the risk of inflammation of the liver (metabolic dysfunction-associated steatohepatitis, also known as MASH), permanent liver damage (cirrhosis), and liver cancer (hepatocellular carcinoma) in people with MASLD.

Other disorders

The I148M change in the PNPLA3 enzyme has also been associated with the worsening of other liver diseases, such as a viral infection called hepatitis C. The variant also increases the risk of liver damage in people with alcohol use disorder. The mechanism of this effect is not well understood, but the altered PNPLA3 enzyme appears to increase the amount of scar tissue (fibrosis) on the liver in people with these conditions.

Other Names for This Gene

  • acylglycerol O-acyltransferase
  • adiponutrin
  • ADPN
  • C22orf20
  • calcium-independent phospholipase A2-epsilon
  • patatin like phospholipase domain containing 3

Frequently Asked Questions

Key changes include maintaining a healthy weight, following a balanced diet low in refined sugars and saturated fats, engaging in regular aerobic exercise, limiting alcohol intake, and controlling blood sugar and cholesterol levels. Regular liver function tests can help track progress.
Carriers of the variant have a modestly higher risk of progressing to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Monitoring should involve periodic liver function tests, imaging such as ultrasound or elastography, and, if indicated, alpha‑fetoprotein screening. Discuss a personalized surveillance plan with your hepatologist.
The PNPLA3 gene codes for an enzyme that helps regulate the creation and breakdown of fats in liver cells. The I148M variant changes a single amino acid in the enzyme, reducing its activity. This leads to less efficient fat turnover, causing fat to build up in the liver and increasing the risk of metabolic dysfunction‑associated steatotic liver disease (MASLD).
Testing is done with a simple blood draw or saliva sample that is sent for DNA sequencing or a targeted SNP test. A positive result indicates a higher genetic predisposition to liver fat accumulation, but it does not guarantee disease. It signals that you should monitor liver health more closely and adopt preventive lifestyle measures.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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