Patatin-Like Phospholipase Domain-Containing 3/Adiponutrin Deficiency in Mice Is Not Associated with Fatty Liver Disease†,‡

Abstract PNPLA3 (adiponutrin), a novel patatin-like phospholipase domain-containing enzyme, is expressed at high level in fat, but also in other tissues including liver. Polymorphisms in PNPLA3 have been linked to obesity and insulin sensitivity. Notably, a nonsynonymous variant rs738409(G) allele of the PNPLA3 gene was found to be strongly associated with both nonalcoholic and alcoholic fatty liver disease. We have generated Pnpla3 −/− mice by gene targeting. Loss of Pnpla3 has no effect on body weight or composition, adipose mass, or development, whether the mice were fed regular chow or high-fat diet or bred into the genetic obese Lep ob/ob background. Plasma and liver triglyceride content and plasma aspartate aminotransferase and alanine aminotransferase levels were not different between Pnpla3 +/+ and Pnpla3 −/− mice while they were on regular chow, fed three different fatty liver-inducing diets, or after they were bred into Lep ob/ob background. Hepatic Pnpla5 messenger RNA (mRNA) levels were similar in wild-type and Pnpla3 −/− mice, although adipose Pnpla5 mRNA level was increased in Pnpla3 −/− mice. A high-sucrose lipogenic diet stimulated hepatic Pnpla3 and Pnpla5 mRNA levels to a similar degree, but it did not affect adipose or liver triglyceride lipase (ATGL, known also as Pnpla2) mRNA in Pnpla3 +/+ and Pnpla3 −/− mice. Finally, Pnpla3 +/+ and Pnpla3 −/− mice displayed similar glucose tolerance and insulin tolerance tests while on regular chow or three different fatty liver–inducing diets. Conclusion: Loss of Pnpla3 does not cause fatty liver, liver enzyme elevation, or insulin resistance in mice.