**1. Introduction**

366 Dyslipidemia - From Prevention to Treatment

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The pioneering work of Hans Selye (1936) led to the use of the word "stress" in a biological context gaining popularity world-wide. Stress is as an organic response to stressors that can be aversive stimuli or unknown situations capable of compromising homeostasis. During the stress reaction, the sympathetic nervous system and hypothalamic–pituitary–adrenal axis are stimulated. Consequently, serum concentrations of classical stress hormones, namely catecholamines and glucocorticoids, are increased and act on cells and tissues inducing adaptive changes in order to protect the organism and allow its survival. In addition, the stress reaction can also modulate immune system activities and the secretion of other hormones (gonadotrophins, estrogen, testosterone, thyroid, angiotensins).

Considering that organic homeostatic systems are subject to frequent environmental and internal variations, Sterling and Eyer (1988) proposed the term alostasis to describe the adaptative processes that actively maintain stability through physiological changes.

The terms eustress and efficient allostasis describe facile adaptation, such as a quick peak stress response to mobilize energy to deal with an acute stressor, and a rapid return to baseline, when the stressor terminates. On the other hand, distress or allostatic load refers to an imbalance in systems that promote adaptation (Epel, 2009; Korte et al., 2005). This imbalance can simply be the result of too much repeated stress, but it can also be the result of adaptative systems that are out of balance and fail to shut-off or, alternatively, systems that fail to return to normal (Epel, 2009). Therefore the shut-off of the stress response is particularly important, because, when systems do not shut off in time, they can cause damage or promote pathology (McEwen, 1998).

The classical stress hormones, glucocorticoids (cortisol) and catecholamines (epinephrine and norepinephrine), are catabolic and modulate the breakdown of glycogen, triglycerides and proteins into molecules that can be rapidly metabolized in order to generate energy (Black, 2002). These responses enable energy substrates to be directed to organs and tissues

<sup>\*1</sup>*Department of Physiological Sciences, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil 2Science and Technology Institute, Federal University of São Paulo, São José dos Campos, Brazil 3Life Sciences Center, Pontifical Catholic University of Campinas, Campinas, Brazil 4Division of Pharmacy, Faculty of Americana, Americana, Brazil* 

*<sup>5</sup>Department of Medicine, Federal University of São Paulo, São Paulo, Brazil*

Dyslipidemia Induced by Stress 369

triglycerides are secreted by the liver in large quantities within the VLDL particles (Black, 2003). Therefore both catecholamines and glucocorticoids antagonize the actions of insulin, contributing to insulin resistance (Kyrou & Tsigos, 2009; Lafontan & Langin,

Moreover, hyperinsulinemia acts centrally to stimulate sympathetic nervous system activity, resulting in increased secretion of catecholamines (Black, 2003), and the absence of satisfactory insulin action facilitates the actions of cortisol and glucagon, which in turn stimulate phosphatidate phosphohydrolase activity to synthesize hepatic triglyceride

The cortisol also induces apoprotein B (apo B) secretion from the liver in the proportion of one apo B molecule per VLDL particle (Brindley et al., 1993), consequently increasing the VLDL concentrations in the bloodstream. As each VLDL particle is metabolized to intermediate-density lipoprotein (IDL) or LDL, the action of the cortisol that stimulates apo B secretion also results in increased LDL particles in the blood. Furthermore, in the presence of stress-induced insulin resistance, high levels of glucocorticoids suppress the hepatic LDL

Contributing to all these processes, it has been shown that perilipin, which coats the surface of lipid droplets to restrict lipase access to the triglyceride core within the droplet, may suffer phosphorylation and/or down-regulation by glucocorticoid action, thereby facilitating the lipolysis of triglycerides in fatty acids and glycerol (Xu et al., 2001). This sets off a vicious cycle, leading to more and more triglycerides being produced by the liver and secreted in VLDL particles, as a result of the stimulation of glucocorticoids and

In addition, norepinephrine and cortisol inhibit lipoprotein lipase activity, leading to diminished triglyceride clearance, decrease in HDL concentration, and increase in VLDL, IDL, and LDL concentrations in the bloodstream (Stoney, 2007). Norepinephrine also diminishes hepatic triglyceride lipase activity, which in turn promotes high concentrations

In the context of stress-induced dyslipidemia, changes in food ingestion must also be considered. During acute stress, transient dyslipidemia and food intake inhibition are mediated by β-adrenergic activation and increased hypothalmic corticotrophin releasing hormone (CRH) levels which act as catabolic signals. On the other hand, chronic activation of the hypothalamic-pituitary-adrenal axis has been associated with overeating and obesity (Dallman et al., 2004; Nishitani & Sakakibara, 2006). Many studies have supported this relationship. Lemieux & Coe, 1995, related that approximately 50% of women with posttraumatic stress disorder as a result of childhood sexual abuse were overweight, and also showed high concentrations of norepinephrine, epinephrine, and dopamine in urine. Changes in sleep-wake cycles associated with stress, resulting in sleep loss, induce decreased leptin levels, increased ghrelin levels, and increased hunger and appetite (Pejovic et al., 2010; Spiegel et al., 2004). In addition, the parent's lifestyle can influence metabolism, and individuals exposed to maternal stress during intrauterine life can exhibit deregulation of body weight control mechanisms and blood lipid profile (De Moura, 2008). The relationship between excessive glucocorticoids and visceral fat accumulation has also been

Thus, the typical response to chronic stress is not by way of avoiding food but by increasing the intake of sugar- and fat-rich comfort foods, which make people feel better

2009).

(Brindley et al., 1993).

fatty acids.

receptors, which delay LDL clearance (Stoney, 2007).

of lipoproteins rich in triglycerides in the blood (Stoney, 2007).

discussed by Björntorp & Rosmond, 1999.

with the greatest demand during the stress reaction, and support the fight or flight reaction to a stressor.

During acute stress, there is a rapid and transient increase in blood concentrations of total cholesterol, low-density lipoprotein (LDL), apoprotein B, triglycerides, and free fatty acids (Stoney, 2007). This increase persists as along as the stressor is maintained (Black, 2002), and disappears in stress-free periods (Stoney et al., 1999). In chronic stress situations, it has been shown that dyslipidemia is maintained and may persist even after the stressor is no longer present (Neves et al., 2009).
