Our data clearly support that both p53 and SIRT6 mRNA and protein levels increase in response to PA treatment, and that p53 cooperates with SIRT6 to upregulate the CL de novo biosynthesis-related genes CDS1 and CDS2. These data indicate that p53 and SIRT6 may protect against PA-induced metabolic disorders and have important roles in maintaining lipid homeostasis. Here, SIRT6 is linked to metabolic disease.