HC diet inhibited testosterone synthesis by activating endoplasmic reticulum stress in testicular Leydig cells

Abstract

Emerging epidemiological studies indicate that hypercholesterolaemia is a risk factor for testosterone deficiency. However, the underlying mechanism is unclear. Testicular Leydig cells are the primary source of testosterone in males. To identify the effect and mechanism of cholesterol overload on Leydig cell function, rats were fed with a HC (HC) diet to induce hypercholesterolaemia. During the 16‐week feeding period, serum testosterone levels were reduced in a time‐dependent manner in rats fed the HC diet. Accordingly, these steroidogenic enzymes within the Leydig cells, including steroidogenic acute regulatory protein (StAR), cholesterol side‐chain cleavage cytochrome P450 (P450scc) and 3β‐hydroxysteroid dehydrogenase (3β‐HSD), were down‐regulated. Notably, the HC‐fed rats showed evident endoplasmic reticulum (ER) stress in the testis, including a dilated ER as an evident pathological change in the Leydig cell ultrastructure, up‐regulated ER stress biomarker (binding immunoglobulin protein) levels and activation of the activating transcription factor 6 (ATF6)‐related unfolded protein response pathway. Further analysis showed that when 4‐phenyl butyric acid (4‐PBA) was used to block ER stress in HC‐fed rats for 8 weeks, the testosterone deficiency was significantly alleviated. Our findings suggested that high dietary cholesterol intake affected serum testosterone levels by down‐regulating steroidogenic enzymes and that activated ER stress might serve as the underlying mechanism.

Orlistat attenuates obesity‐induced decline in steroidogenesis and spermatogenesis by up‐regulating steroidogenic genes

“…We speculate that suppression of the expression of steroidogenic genes such as StAR and CYP11A1, which catalyse the rate‐limiting step of steroidogenesis, and the decreased transcript levels of genes encoding for CYP17A1, 3β‐HSD and 17β‐HSD are responsible for the decreased levels of testosterone in the present study. Studies in which decreases in the mRNA levels of these genes were reported, have corroborated our findings 6,67 . The observed steroidogenesis decline, together with deregulation of the HPG axis, may account (in part) for the impaired spermatogenesis, since the latter process depends largely on the HPG axis for its maintenance and regulation.…”

“…CYP11A1 catalyses the first and rate‐limiting step in testosterone biosynthesis, that controls the transformation of cholesterol to pregnenolone in the mitochondrion, while 17β‐HSD controls the transformation of progesterone to testosterone in the endoplasmic reticulum. LH on the other hand, is the main extrinsic factor acting through the HPG axis to regulate steroidogenesis 6 …”

“…The synthesis of steroid hormones is carried out using cholesterol found mainly in diets 6 . However, several studies have indicted hypercholesterolaemia as the principal cause of mortality and morbidity in diseases such as cardiovascular disease, cancer, non‐alcoholic fatty liver disease and Alzheimer's disease 7 .…”

Cyclophilin D participates in the inhibitory effect of high‐fat diet on the expression of steroidogenic acute regulatory protein

“…The Leydig cells, which are located between the seminiferous tubules of the testis, are responsible for the synthesis and secretion of testosterone. Our previous studies have reported that dietary factors such as high‐cholesterol diets could inhibit Leydig cell steroidogenesis . In this study, we demonstrated that the high‐fat diet could induce lipid accumulation in testicular Leydig cells.…”

“…Our previous studies have reported that dietary factors such as high-cholesterol diets could inhibit Leydig cell steroidogenesis. 33 In this study, we demonstrated that the high-fat diet could induce To investigate the effects of lipid overload on testicular Leydig cells, the HFD mouse model was used to show that the weight of mice in the HFD group increased obviously, accompanied by dyslipidaemia and increased adipose tissue. In this model, diet-induced dyslipidaemia, characterized by rising in TC, LDL-C and HDL-C, was in line with the study of Fan Yong et al 9 Even in these animal experiments, there was no significant difference in TG levels, and these above results still demonstrated the success of the construction of HFD mouse model simulating a similar human condition.…”