Poly(ADP-ribose) polymerase-2 is a lipid-modulated modulator of muscular lipid homeostasis

There is a growing body of evidence that poly(ADP-ribose) polymerase-2 (PARP2), although originally described as a DNA repair protein, has a widespread role as a metabolic regulator. We show that the ablation of PARP2 induced characteristic changes in the lipidome. The silencing of PARP2 induced the expression of sterol regulatory element-binding protein-1 and -2 and initiated de novo cholesterol biosynthesis in skeletal muscle. Increased muscular cholesterol was shunted to muscular biosynthesis of dihydrotestosterone, an anabolic steroid. Thus, skeletal muscle fibers in PARP2−/− mice were stronger compared to those of their wild-type littermates. In addition, we detected changes in the dynamics of the cell membrane, suggesting that lipidome changes also affect the biophysical characteristics of the cell membrane. In in silico and wet chemistry studies, we identified lipid species that can decrease the expression of PARP2 and potentially phenocopy the genetic abruption of PARP2, including artificial steroids. In view of these observations, we propose a new role for PARP2 as a lipid-modulated regulator of lipid metabolism. •The genetic deletion of poly(ADP-ribose)-2 (PARP2) induces characteristic changes in the lipidome.•In PARP2 knockout mice SREBP1 and SREBP2 is overexpressed in skeletal muscle leading to higher muscular cholesterol biosynthesis.•Higher muscular cholesterol is shunted to muscular DHT synthesis, but does not lead to systemic increases in DHT levels.•The muscles from PARP2 knockout mice are stronger as compared to the ones derived from wild type littermates.•The expression of PARP2 is regulated by cholesterol derivatives.