Oxidized-LDL inhibits testosterone biosynthesis by affecting mitochondrial function and the p38 MAPK/COX-2 signaling pathway in Leydig cells

Jun Jing,Siyuan Cao,Kuan Liang,Rujun Ma,Shuxian Wang,Ning Ding,Xie Ge,Allan Zijian Zhao,Xuan Huang,Kadiliya Jueraitetibaike,Dandan Wang,Jinzhao Ma,Bing Yao

doi:10.1038/s41419-020-02751-z

Abstract

Abnormal lipid/lipoprotein metabolism induced by obesity may affect spermatogenesis by inhibiting testosterone synthesis in Leydig cells. It is crucial to determine which components of lipoproteins inhibit testosterone synthesis. Circulating oxidized low-density lipoprotein (oxLDL), the oxidized form of LDL, has been reported to be an independent risk factor for decreased serum testosterone levels. However, whether oxLDL has a damaging effect on Leydig cell function and the detailed mechanisms have been rarely studied. This study first showed the specific localization of oxLDL and mitochondrial structural damage in testicular Leydig cells of high-fat diet-fed mice in vivo. We also found that oxLDL reduced the mitochondrial membrane potential (MMP) by disrupting electron transport chain and inhibited testosterone synthesis-related proteins and enzymes (StAR, P450scc, and 3β‑HSD), which ultimately led to mitochondrial dysfunction and decreased testosterone synthesis in Leydig cells. Further experiments demonstrated that oxLDL promoted lipid uptake and mitochondrial dysfunction by inducing CD36 transcription. Meanwhile, oxLDL facilitated COX2 expression through the p38 MAPK signaling pathway in Leydig cells. Blockade of COX-2 attenuated the oxLDL-induced decrease in StAR and P450scc. Our clinical results clarified that the increased serum oxLDL level was associated with a decline in circulating testosterone levels. Our findings amplify the damaging effects of oxLDL and provide the first evidence that oxLDL is a novel metabolic biomarker of male-acquired hypogonadism caused by abnormal lipid metabolism.

Highlights

Leydig cells are steroidogenic cells present in the interstitial compartment of the testes and mainly contribute to testosterone synthesis and secretion[1]
HFD decreased testosterone production and induced testicular damage in mice To determine the function of oxidized low-density lipoprotein (oxLDL) in Leydig cells, we first established a model by feeding a high-fat diet to 8-week-old B6 mice
The testicular structures were abnormal in the HFD-fed group; the seminiferous tubules were separated from the loose interstitial area, and the number of germ cells in the tubules was significantly decreased

Summary

Introduction

Leydig cells are steroidogenic cells present in the interstitial compartment of the testes and mainly contribute to testosterone synthesis and secretion[1]. Secreted testosterone diffuses into the seminiferous epithelium and signals through the androgen receptor in Sertoli cells[2], supporting spermatogenesis processes such as the maintenance of the Increasing evidence from both epidemiological and clinical studies have indicated that a higher prevalence of metabolic syndrome, which is a constellation of low Official journal of the Cell Death Differentiation Association. Jing et al Cell Death and Disease (2020)11:626 high-density lipoprotein cholesterol (HDL-C), and increased very-low-density lipoprotein (VLDL) and triglyceride (TG) levels, was along with lower testosterone[12]. Lipid metabolism disorder may affect spermatogenesis by inhibiting testosterone synthesis in Leydig cells. It has been reported that the level of lipid/lipoprotein are negatively associated with plasma testosterone in male mice[16]. The implicit factors and precise mechanisms by which components of the lipoproteins affect Leydig cell function are still unknown

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Conclusion