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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. Ongoing research will show how this change in PNPLA3 and other genetic changes contribute to the development of MASLD and its complications.
More About This Health ConditionOther 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 PMPLA3 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
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Abdelsattar S, Al-Amodi HS, Kamel HFM, Kasemy ZA, Darwish E, Mosbeh A, Sakr AA, Elgazzar HM, Abdelkareem M, Abozeid M, Zewain SK, Bedair HM, Abdelmageed SM. Impact of genotyping (PTPN2, rs2542151) and (MBOAT7, rs641738) in prediction of fibrosis in Metabolic dysfunction- associated steatotic liver disease' patients. Front Endocrinol (Lausanne). 2025 Sep 11;16:1615162. doi: 10.3389/fendo.2025.1615162. eCollection 2025. Citation on PubMed
- Caligiuri A, Gentilini A, Marra F. Molecular Pathogenesis of NASH. Int J Mol Sci. 2016 Sep 20;17(9):1575. doi: 10.3390/ijms17091575. Citation on PubMed or Free article on PubMed Central
- Chen LZ, Xin YN, Geng N, Jiang M, Zhang DD, Xuan SY. PNPLA3 I148M variant in nonalcoholic fatty liver disease: demographic and ethnic characteristics and the role of the variant in nonalcoholic fatty liver fibrosis. World J Gastroenterol. 2015 Jan 21;21(3):794-802. doi: 10.3748/wjg.v21.i3.794. Citation on PubMed or Free article on PubMed Central
- Dongiovanni P, Donati B, Fares R, Lombardi R, Mancina RM, Romeo S, Valenti L. PNPLA3 I148M polymorphism and progressive liver disease. World J Gastroenterol. 2013 Nov 7;19(41):6969-78. doi: 10.3748/wjg.v19.i41.6969. Citation on PubMed or Free article on PubMed Central
- Elmansoury N, Megahed AA, Kamal A, El-Nikhely N, Labane M, Abdelmageed M, Daly AK, Wahid A. Relevance of PNPLA3, TM6SF2, HSD17B13, and GCKR Variants to MASLD Severity in an Egyptian Population. Genes (Basel). 2024 Apr 4;15(4):455. doi: 10.3390/genes15040455. Citation on PubMed
- Linden D, Tesz G, Loomba R. Targeting PNPLA3 to Treat MASH and MASH Related Fibrosis and Cirrhosis. Liver Int. 2025 Apr;45(4):e16186. doi: 10.1111/liv.16186. Epub 2024 Nov 28. Citation on PubMed
- Mancina RM, Valenti L, Romeo S. Human genetics of steatotic liver disease: insights into insulin resistance and lipid metabolism. Nat Metab. 2025 Nov;7(11):2199-2211. doi: 10.1038/s42255-025-01394-8. Epub 2025 Oct 17. Citation on PubMed
- Severson TJ, Besur S, Bonkovsky HL. Genetic factors that affect nonalcoholic fatty liver disease: A systematic clinical review. World J Gastroenterol. 2016 Aug 7;22(29):6742-56. doi: 10.3748/wjg.v22.i29.6742. Citation on PubMed or Free article on PubMed Central
- Tavaglione F, Pennisi G, Pelusi S. PNPLA3 I148M and Hepatocellular Carcinoma. Liver Int. 2025 Apr;45(4):e70051. doi: 10.1111/liv.70051. Citation on PubMed
- Yu J, Marsh S, Hu J, Feng W, Wu C. The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background. Gastroenterol Res Pract. 2016;2016:2862173. doi: 10.1155/2016/2862173. Epub 2016 May 9. Citation on PubMed or Free article on PubMed Central
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