CONICET | Buscador de Institutos y Recursos Humanos

Rabbit model of Hypercholesterolemia and protection by olive oilHypercholesterolemia (HC) triggers deleterious effects on several tissues defining an important medical and epidemiologic entity [1]. Recently, it has also been reported together with obesity as a risk factor for male infertility [2, 3]. Although several studies have evaluated the effect of HC on semen quality, there are few reports concerning the influence of cholesterol enriched diets on the cholesterol-regulation machinery (CRM) in the seminiferous tubule. Interesting, extra virgin olive oil (EVOO) could revert the changes promoted by HC (citas nuestras). Classic rabbit models for the study of human atherosclerosis were established in New Zealand White (NZW) or Wattanabe (WHHL) rabbits, which have undoubtedly led to many advances in the history of atherosclerosis studies [4]. Interestingly, the rabbit's lipid metabolism is quite similar to that of human and cholesterol-rich diets cause physiological changes that promote atherosclerosis [5]. We developed a HC animal model in NZW rabbits [6, 7, 8, 9] to assess the influence of cholesterol-enriched diets on sperm CRM occurring inside the seminiferous tubules of testis. On a standard chow diet, NZW do not develop spontaneous atherosclerosis because of their low cholesterolemia (30?90 mg/dl [10]). It is generally recommended that feeding rabbits a cholesterol diet of up to 0.5% results in reasonable elevation (compared to human HC) of plasma cholesterol. In our model, rabbits were fed a standard rabbit diet alone or with 14% fat (0.05 % cholesterol) added for 3, 6 and 12 months. Many authors have analyzed the addition of natural products to the rabbit diet to reduce or protect animals from vascular injury [11, 12, 13, 14]. But few have studied its protective effect on seminal parameters altered by HC. Olive oil (OO), a component of Mediterranean diet, has been proposed as a protective agent against vascular injury promoted by acquired HC [15]. We evaluated whether the administration of EVOO (7%) can recover the altered parameters in HC rabbits.The Effects of High Cholesterol on the Rabbit?s BodyExcessive intake of fat diet induced HC, hypertension and disturbed cholesterol homeostasis in the body [16]. We previously reported that in rabbits it also promoted seminal alterations: decrease in semen volume, increase in sperm morphological abnormalities, and depressed sperm functionality, among others [4, 6]. The latter were related to a significant increase in cholesterol content inside the cells of the seminiferous tubule. For this reason we aimed to study the CRM in testis under a hypercholesterolemic environment.Cholesterol-regulating machinery and SREBPDynamic cholesterol regulation is crucial for both testosterone production and spermatogenesis. However, its effect on testicles and specially on the CRM has not yet been fully addressed. Cellular CMR in mammals is controlled by a transcription factor called sterol regulatory element-binding protein 2 (SREBP- 2) [cita]. This protein, which is synthesized as precursor, is inserted into the endoplasmic reticulum membrane. In sterol-deficient cells, proteolytic cleavage of SREBP-2 occurs, thereby releasing its N-terminal mature and active form and enabling to enter the nucleus, where it activates genes involved in cholesterol biosynthesis, as LDL receptor and HMG-CoA reductase.We studied the expression of SREBP and target molecules by western blot and PCR in the testis of HC rabbits and OO-protected animals. The fat diet caused a short-term decrease in CRM, showing that the testicle responds to the fat injury (Figure 1). However, when the diet was extended for 12 months, the fatty environment in the testicle provoked deregulation of the pathway and increased expression of all molecules involved (Figure 2). The OO caused an inverse effect to that of the fat diet (Figure 1 and 2). By immunofluorescence, we detected the nuclear translocation of the active portion of SREBP-2 (Figure 3). Estas figuras son las rotaciones tridimensionales?ConclusionThe rabbit is an optimal animal model to study the relationship between the high-fat diet, hypercholesterolemia and infertility. The chronic administration of a diet rich in fats promotes changes at the plasma, tissue and seminal levels. These processes are related to failures at the general level of cholesterol metabolism regulation, which cause hypercholesterolemia and accumulation of cholesterol in body cells, including the testicle. This increase in cellular cholesterol has a deleterious effect on the sperm cell, affecting its morphology and functionality. All these alterations are reversed by the addition of olive oil to the diet that recuperates plasma cholesterol level, recovers the regulation of intracellular cholesterol metabolism and improves testicular spermatogenesis.