Transporte postprandial de ácido oleanólico en adolescentes y su acción terapéutica sobre monocitos-macrófagos THP-1

Abstract

The concept of metabolic syndrome (MetS) has been consolidated throughout the 20th century and consists of a set of cardiometabolic abnormalities that increase the risk of developing type 2 diabetes mellitus and cardiovascular disease (CVD). There is consensus that obesity, insulin resistance (IR), dyslipidemia and arterial hypertension constitute the essential components of this syndrome. The worldwide prevalence of obesity in the adolescent population has quadrupled in the last forty years. Furthermore, adolescents with abdominal obesity are more likely to remain obese in adulthood and, therefore, to develop cardiovascular events. Approximately 18 million people die annually as a result of CVD. It has been proposed that the widespread morbidity and mortality as a consequence of CVD could be reduced by early identification in children and adolescents of MetS or its components on an individual basis. In this line, the diagnostic criteria for MetS allow its categorization, the assessment of its related components, and the evaluation of long-term cardiovascular risk. Despite the development in recent years by different authors of specific criteria for the child and adolescent population, the changes related to pubertal growth and development in adolescence give rise to cut-off points without established fixed values, which makes it difficult to create and apply homogeneous and unified criteria for MetS. In addition to correct screening for MetS in adolescents in order to have optimal control of the health and epidemiological repercussions of this syndrome, it is also essential to search for new therapeutic and preventive strategies to complement the existing ones. In recent years, there has been increasing interest in the properties and therapeutic effects of certain bioactive compounds. Among them is the Oleanolic Acid (OA), a pentacyclic triterpene available in large quantities in the olive leaf, and to a lesser extent in olive oil. This triterpene has anti-inflammatory, antihypertensive, antioxidant, insulin-sensitizing, lipid-lowering and hypoglycemic properties that give it great potential for the control of each of the components of MetS. However, the molecular mechanisms underlying these properties are not yet widely understood The therapeutic potential of OA depends on its bioavailability and transport mechanisms. It is a compound that is practically insoluble in aqueous media and partially soluble in lipophilic matrices. In fact, the postprandial presence of OA in blood plasma after ingestion of an oil formulation enriched in this triterpene has been demonstrated in humans. It is also known to be transported bound to albumin, but it is not known whether it is transported as part of triglyceride-rich lipoproteins (TRLs) after intestinal absorption. Taking all this evidence into account, the general objectives of this International Doctoral Thesis are to characterize and define MetS in adolescents (study I); to analyze the therapeutic effects of OA on THP-1 monocyte-macrophages, as well as on foam cell formation (studies II, III and IV); and to study the mechanisms of postprandial transport of OA in healthy and normal-weight adolescents (study V). A study with a cross-sectional design was carried out in 981 Spanish adolescents to contrast the degree of agreement between eight different criteria for defining MetS in the adolescent population (study I). Two systematic reviews were also carried out, the first (study II) to analyze the effects of OA on the components of MetS and on inflammatory markers and biomarkers of oxidative stress; and the second (study III) to determine the effects of OA on the molecular mechanisms and signaling pathways involved in the development of IR and the underlying oxidative stress. Finally, a postprandial, controlled, randomized, double-blind, controlled trial was developed in 22 healthy, normal-weight adolescents to determine the presence of OA in human postprandial TRLs (study V), as well as to assess the effects of OA after foam cell formation with TRLs (study IV). The effects of different concentrations of OA on THP-1 macrophages stimulated with LPS were also analyzed (study IV). The results of the present Doctoral Thesis showed discrepancies in the degree of concordance between the eight criteria used in the adolescent population. These data suggest the need to advance in the validation of uniform and homogeneous diagnostic criteria that facilitate their use in the clinical practice. Regarding the therapeutic effects of OA, the results show its efficacy in the control of certain components of MetS, being remarkable its ability to attenuate IR and the underlying oxidative stress through its modulatory activity on the IRS/PI3K/Akt/FoxO1 insulin signaling pathway and MAPK pathways. Likewise, experimental studies have observed the capability of OA to attenuate the inflammatory state and increase AMPK-α levels in LPS-induced THP-1 macrophages, and to decrease IL-6 and Akt levels in foam cells. Finally, despite observing evidence of the presence of OA in TRLs, these results should be considered preliminary and, therefore, future postprandial trials that delve deeper into the postprandial transport of AO are needed. The findings of this PhD Thesis reinforce the potential of AO to prevent and treat IR, atherogenic alterations and different metabolic factors underlying MetS in adolescents through the use of functional olive oils.