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

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.

Chronic stress inhibits testosterone synthesis in Leydig cells through mitochondrial damage via Atp5a1

“… 7 Lipoprotein metabolism induced by obesity disrupts the electron transport chain and ultimately leads to reduced mitochondrial membranes and inhibits testosterone biosynthesis in Leydig cells. 8 In addition, acetamiprid drugs have a similar effect. 9 Thus, mitochondrial dysfunction has been speculated to be closely associated with testosterone synthesis and male reproduction.…”

“…Testosterone has been reported to regulate the expression of mitochondrial genes and alleviate oxidative damage, 6 and mitochondrial antioxidants protect steroidogenesis, on the basis of the expression of testosterone and its related steroid synthase 7 . Lipoprotein metabolism induced by obesity disrupts the electron transport chain and ultimately leads to reduced mitochondrial membranes and inhibits testosterone biosynthesis in Leydig cells 8 . In addition, acetamiprid drugs have a similar effect 9 .…”

Synthesis and biological evaluation of new 1,4‐benzothiazine derivatives as potential COX‐2 inhibitors

“…[13] Further, recent study verified that knockdown of COX-2 attenuated the oxLDL induced suppression of StAR and P450scc protein in TM3 Leydig cells. [14] In the present study, LC-540 Leydig cells have been used to study the efficacy of benzothiazine as COX-2 inhibitors. The promising result of this study shows that compound 5i significantly inhibits both the gene and protein expressions of COX-2.…”

NF-κB-repressed Sirt3 mediates testicular cholesterol metabolism and cytoskeleton assembly via P450scc/SOD2 deacetylation during spermatogenesis

“…Except for SOD2, Mel also regulated P450scc deacetylation by the interaction of SIRT3 and P450scc in testis. P450scc, as a catalyst converting cholesterol to pregnenolone, is indispensable for testosterone biosynthesis (Jing et al, 2020). Besides, the data showing that Mel reversed NF-κB p65 Ser536 phosphorylation in Cd-treated rat testis, is consistent with the work by Liu et al, who manifested that Mel blocked NF-κB p65 signal in mice adipose tissue (Liu et al, 2017b).…”