Sirt1 regulates testosterone biosynthesis in Leydig cells via modulating autophagy
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Protein & Cell
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Dear Editor, Steroid hormones are crucial signal molecules that regulate a large number of physiological and developmental processes. Testosterone is the key steroid hormone required for the development of male characteristics and also supports the physiology of the male reproductive system (Sinclair et al., 2015). Testosterone is primarily produced by the Leydig cells residing in the testicular interstitium. The cholesterol acts as a substrate for the biosynthesis of testosterone. Since steroidogenic cells are capable of storing only very little hormone, rapid synthesis of hormone requires the mobilization of the precursor cholesterol, chiefly stored as intracellular lipid droplets (LDs) (Danielsen et al., 2016). Leydig cells are the major sites to produce testosterone, there are extremely active autophagy in them, and a decline in steroidogenesis has also been associated with the decline of autophagic flow. Moreover, the disruption of autophagy leads to decreased intracellular LDs, and therefore affects testosterone synthesis in the Leydig cells (Danielsen et al., 2016; Gao et al., 2018). Sirtuin 1 (SIRT1) is one of the members of NAD-dependent protein deacetylase which regulates multiple cellular functions such as metabolism, apoptosis, and autophagy (Cohen et al., 2004; Chang et al., 2015). SIRT1 is necessary for fertility in mice, it participates in the differentiation of spermatogenic stem cells, acrosome biogenesis, and histone-to-protamine transition during spermatogenesis (Liu et al., 2017). However, the functional role and underlying mechanism of SIRT1 in testosterone biosynthesis are yet unknown. To explore the role of Sirt1 in testosterone biosynthesis, Sirt1F/F mice were crossed with SF1-Cre mice to generate steroidogenic cell-specific Sirt1-knockout mice, and the knockout efficiency of SF1-Sirt1−/− mice was further confirmed by Western blot (Fig. 2E). We found no difference in testis morphology (Fig. S1A) and the sperm count in cauda epididymis (Fig. S1B) of Sirt1F/F and SF1-Sirt1−/− mice. However, the mating efficiency and pregnancy rate of SF1Sirt1−/− mice were significantly decreased compared to Sirt1F/F mice (Fig. S2). To investigate reduced mating efficiency and docile behavior, we carried out sexual behavior analysis. SF1-Sirt1−/− mice showed a significantly longer
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latency (Fig. 1A) and mounted targeted females less frequently and with a shorter mounting duration (Fig. 1B and 1C) compared to the Sirt1F/F mice. However, sniffing frequency and duration was not significantly affected in SF1Sirt1−/− mice compared to control mice (Fig. 1D and 1E). In vertebrates, male sexual behavior is regulated by testosterone, thus we measured the serum testosterone concentration and found reduced testosterone levels in the sera of SF1-Sirt1−/− mice (Fig. 1F). Testosterone levels were also significantly reduced in the Leydig cells of SF1-Sirt1−/− mice (Fig. 1G). Together, these findings suggest that Sirt1-disruption results in a sharp decrease in testosterone and influence the sexu
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