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

Abstract

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 role of ADP-ribose metabolism in metabolic regulation, adipose tissue differentiation, and metabolism

“…PARPs interfere with hormonal signaling at various points. PARPs regulate hormone levels, including intramuscular androgen production (Marton et al 2018b). Fasting serum insulin levels were lower in PARP2 knockout mice (Bai et al 2011a), weak PARP inhibitors were shown to restore insulin expression (Ye et al 2006) and the deletion of Tankyrase 1 (PARP5a, TNK1) induced serum insulin levels (Yeh et al 2009).…”

“…PARP1 and PARP2 activation were shown to be a key step in the development of insulin resistance (for review, see Bai and Cantó 2012). Hormones, such as insulin (Horvath et al 2008), estrogens (Mabley et al 2005;Jog and Caricchio 2013;Joshi et al 2014), androgens (Shimizu et al 2013), progesterone (Ghabreau et al 2004), artificial steroids, and vitamin D (Marton et al 2018b) can modulate the expression and activity of PARP1 and PARP2. Endocrine disruptors were also shown to modulate PARP activity (Chen et al 2013;Guerriero et al 2018).…”

“…The pattern of polyunsaturated fatty acid metabolites is dysregulated in PARP1 knockout mice (Kiss et al 2015) and there seems to be a correlation between PARP1 activity and erythrocyte membrane composition (Bianchi et al 2016). Furthermore, the composition of membrane-constituent lipids was altered upon the deletion of PARP2 (Marton et al 2018b). Fatty acid absorption and fatty acid biosynthesis had not been studied in the context of PARP enzymes and poly-ADP-ribosylation; however, the involvement of PARPs is likely, as suggested by scattered data in the literature.…”

“…PARP2 negatively regulates de novo cholesterol biosynthesis through suppression of sterol-regulatory element-binding protein expression. The deletion of PARP2 induces increased cholesterol biosynthesis in the liver and skeletal muscle (Szántó et al 2014;Marton et al 2018b). A fraction of excess cholesterol seems to be incorporated into biomembranes (Marton et al 2018b).…”

“…The deletion of PARP2 induces increased cholesterol biosynthesis in the liver and skeletal muscle (Szántó et al 2014;Marton et al 2018b). A fraction of excess cholesterol seems to be incorporated into biomembranes (Marton et al 2018b). The deletion of PARP2 does not affect the enterohepatic circulation of cholesterol.…”