Epistatic interaction between the lipase-encoding genes Pnpla2 (ATGL) and Lipe (HSL) causes liposarcoma in mice

Liposarcoma is a poorly understood malignancy of fat cells. Lipolysis, a central pathway of adipose tissue metabolism, has been implicated in cancer. Here, we generated tissue-specific single- and combined knockout mice for the two major lipases ATGL and HSL. Notably, double knockout (DAKO) mice developed late onset liposarcoma with complete penetrance, while single knockout mice appeared normal. DAKO whole transcriptome profiles differed from those of single knockout mice, revealing an early-onset tissue-specific response that persisted until the late-onset development of liposarcoma. Cancer-associated markers Gpnmb and G0s2 were among the most highly dysregulated genes in DAKO mice and also in human liposarcomas, suggesting a potential role for these proteins as liposarcoma-specific biomarkers. Taken together, our results demonstrate a novel epistatic interaction linking lipolysis with cancer. DAKO mice provide a promising model for studying early premalignant changes that lead to late-onset disease. Four mouse strains were used: normal controls, mice deficient in adipose tissue for ATGL (ATGLAKO), HSL (HSLAKO) or both (DAKO). HSLAKO mice were homozygous for a floxed allele of Lipe and harbored a transgene, from which Cre is expressed from a Fabp4 promoter that is active in adipose tissues. Further details about creation of HSLAKO mice are provided in supplemental methods. DAKO mice were created by crossing two single knockout mice ATGLAKO and HSLAKO for at least two generations. Mice expressing the Fabp4-Cre transgene were used as controls. In this study, the targeted allele had been transferred for at least 8 generations to a C57BL/6J background.