The Paraoxonase (PON) Gene Family in Health, Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Other Diseases.

The Paraoxonase (PON) gene family consists of three paralogues (PON1, PON2 and PON3) that are tandemly located on chromosome 7. In this review paper, the structure and function of the encoded proteins is summarized. In addition, an overview is given on the generated animal models. Finally, their involvement in the pathogenesis of different diseases is discussed, starting from an extended screening of the literature using PUBMED and Web of Science. PON1 and PON3 are mainly expressed in the liver and released into the bloodstream, bound to high-density lipoprotein. PON2 is expressed in various tissues, including the liver, lungs, heart, placenta and testes, but remains intracellular. The name of the enzyme family reflects PON1's ability to neutralize paraoxon, but they also exhibit lactonase and esterase activities. All three PON enzymes play a role in reducing lipid peroxides in High-Density Lipoproteïne (HDL) and low-density lipoprotein(LDL), giving them antioxidant properties. This links them to Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD), a metabolic liver condition marked by the excessive accumulation of triglycerides (TG) in liver cells. In addition to their association with MASLD, the PON genes are, due to their antioxidant properties, also associated with other conditions including cardiovascular diseases, chronic kidney disease, neurological and immunological conditions up to some forms of cancer. In the latter, the antioxidant properties can result in tumor progression by protecting malignant cells from oxidative damage thus supporting survival, proliferation and metastasis indicating them as potential drug targets for treatment of cancer. Therefore, further research on this protein family can provide novel insights into their function and their potential therapeutic applicability.