Impact of high fat diet on the sterol regulatory element-binding protein 2 cholesterol pathway in the testicle

Abstract

Male fertility has been shown to be dependent on cholesterol homeostasis. This lipid is essential for testosterone synthesis and spermatogenesis, but its levels must be maintained in an optimal range for proper testicular function. In particular, sperm cells development is very sensitive to high cholesterol levels, noticeably during acrosomal formation. The aim of this work was to study whether the molecular pathway that regulates intracellular cholesterol, the Sterol Regulatory Element-Binding Protein (SREBP) pathway, is affected in the testicles of animals under a fat diet. To investigate this, we took advantage of the non-obese hypercholesterolemia (HC) model in New Zealand rabbits that displays poor sperm and seminal quality. The testicular expression of SREBP isoform 2 (SREBP2) and its target molecules 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) and low-density lipoprotein receptor (LDLR) were studied under acute (6 months) and chronic (more than 12 months) fat intake by RT-PCR, western blot and immunofluorescence. Our findings showed that fat consumption promoted down regulation of the SREBP2 pathway in the testicle at 6 months, but upregulation after a chronic period. This was consistent with load of testicular cholesterol, assessed by filipin staining. In conclusion, the intracellular pathway that regulates cholesterol levels in the testicle is sensitive to dietary fats, and behaves differently depending on the duration of consumption: it has a short-term protective effect, but became deregulated in the long term, ultimately leading to a detrimental situation. These results will contribute to the understanding of the basic mechanisms of the effect of fat consumption in humans with idiopathic infertility.

Extra‐virgin olive oil ameliorates high‐fat diet‐induced seminal and testicular disorders by modulating the cholesterol pathway

“…26 In previous works, we found that rabbits fed with HFD showed alterations in the SREBP2 pathway, which promoted a chol accumulation in the testes. 27 This resulted in an almost two-fold chol overload in the ejaculated spermatozoa (110 μg/109 cells for the rabbits on fat diet and 64 μg/109 cells for control rabbits, Saez et al [2013]), in accordance with other authors' reports. 28 Those cells also presented morphological and functional abnormalities.…”

“…To accomplish that, we isolated RNA from rabbit testes and then we monitored the relative expression levels of SREBP2 mRNA. We previously realized that the fat diet provoked a significant increase in both SREBP2 mRNA and protein (Funes et al, 2021). Figure 3A shows that SREBP2 mRNA from the HCR + EVOO group was significantly decreased compared to HCR (p < 0.001).…”

“…However, it is also present and active in different cell types of the seminiferous tubule 26 . In previous works, we found that rabbits fed with HFD showed alterations in the SREBP2 pathway, which promoted a chol accumulation in the testes 27 . This resulted in an almost two‐fold chol overload in the ejaculated spermatozoa (110 μg/109 cells for the rabbits on fat diet and 64 μg/109 cells for control rabbits, Saez et al.…”

“…The constituents of SD were: 17% crude protein, 60.5% carbohydrates, 16% fiber, 0% saturated fat, 5.3% minerals, and 12% water; data from the manufacturer's analysis, GEPSA FEEDSH. HFD was prepared according to previously described protocol, 17,18,27,29,46 consisting of 15% crude protein, 14% fiber, 14% fat (6.5% saturated fat, 0.05% cholesterol). In the case of HFD + EVOO, HFD diet was supplemented with EVOO (7% v/w).…”

Diet and Male Fertility: The Impact of Nutrients and Antioxidants on Sperm Energetic Metabolism

“…In the long term, this short-term protective effect governed by SREBP2 became deregulated. The consequent increase in the membrane levels of cholesterol may be responsible for sperm abnormalities [ 72 ].…”