br Conclusions Although numerous studies support the role
Conclusions Although numerous studies support the role of SIRT1 as a protective factor against damages induced by MG or AGE overload in cells and chronically exposed animal models [, , , , , , , , , ], our results from mouse oocytes in vitro exposed to MG revealed for the first time that SIRT1 can modulate MG scavenging by promoting expression of glyoxalases. Moreover, the finding that up-regulation of glyoxalase is associated with that of components of SIRT1 functional network in the ovaries of MG mice provides strong evidence that SIRT1 participates in the response to methylglyoxal-dependent glycative stress in the female gonad. This response avoids ovarian AGE accumulation and alterations to folliculogenesis, but does not prevent disruption of ovarian and follicle homeostasis required for acquisition of oocyte competence [72,73] and probably responsible for increased embryo T-5224 and foetal resorption . Further studies are needed to establish the effects of long-term MG in vivo administration on the female reproductive system. Although caution should be taken in translating our results in the mouse model to humans, the present study represents a contribution to the knowledge of the effects on fertility of MG and AGE overload during aging, PCOS and diabetes and can help to build up preventive strategies.
Conflicts of interest
Acknowledgments The funds for this work were provided by the Department of Life, Health and Environmental Sciences, University of L'Aquila (RIA 2014-2017) and San Salvatore Hospital, L'Aquila (post-doc fellowship to G.D.).
Introduction Hepatic steatosis is a condition where neutral lipids in the liver accumulate . Hepatic steatosis and related disorders are the most common form of liver disease . The prevalence is rapidly growing as a result of the rising numbers of people with obesity and diabetes . Augmented de novo hepatic lipogenesis, a process regulated by the nuclear receptor liver X receptor (LXR) is associated with an increased risk for hepatic steatosis . The nuclear receptor stimulates the transcription of genes essential for de novo hepatic triglyceride synthesis: acetyl-CoA carboxylase (ACC1), fatty acid synthase (FAS), and stearoyl-coenzyme A desaturase 1 (SCD1) . In addition, LXR is essential in hepatic and macrophage cholesterol metabolism . Upon activation by its oxysterol ligands, LXR transcriptionally activates hepatic genes involved in the conversion of cholesterol to bile acid and the direct secretion of cholesterol into the bile, i.e. cholesterol 7α-hydroxylase, ATP-binding cassette (ABC) transporters G5 (ABCG5) and G8 (ABCG8). In macrophages, LXR stimulates the efflux of cellular cholesterol via ABCA1 and ABCG1 . Thus, in contrast to LXR's harmful role in hepatic steatosis, LXR protects against atherosclerosis by decreasing the accumulation of cholesterol in macrophages and preventing foam cell formation . Protein arginine N-methyltransferase 3 (PRMT3) acts as a specific cofactor for LXR transcription . Studies by Kim et al. have shown that inhibition of PRMT3 function protects against hepatocyte triglyceride accumulation in vitro . We have confirmed a potential role for PRMT3 in the development of hepatic steatosis in a short-term in vivo setting . More specifically, mice treated with the selective PRMT3 antagonist SGC707 were protected from fatty liver development induced by LXR activation using T0901317 and palm oil . Importantly, we noticed that the anticipated reduction in LXR activity upon SGC707 treatment was selective for the hepatic lipogenesis genes, as the LXR-driven genes involved in cholesterol metabolism were not affected by pharmacological blockade of PRMT3 activity. Uncoupling of the two LXR activities is interesting in light of potential therapeutic use of the SGC707 compound. Treatment with SGC707 could theoretically diminish hepatic steatosis, while leaving hepatic and macrophage cholesterol metabolism, important in cholesterol-driven pathologies like atherosclerosis, untouched. To validate this hypothesis, the effect of chronic PRMT3 inhibition through SGC707 treatment was investigated in atherosclerosis-susceptible hyperlipidemic apolipoprotein E (apoE) knockout mice.