**5. Conclusion**

Ability of tissues to adapt morphologically and functionally to different physiological situations determines the overall metabolic health. Increased adipose tissue mass but mainly adipocyte lipid overload is responsible for the "pathogenic" adipose tissue phenotype. This phenotype, characteristic by extra-large unilocular adipocytes, further promotes tissue hypoxia and development of chronic persistent inflammation and metabolic stress. Pathogenic modification of the adipocyte modulates its metabolic, secretory and immunologic function leading to the development of metabolic disease (Fig. 10.). Inactive skeletal muscle, overloaded with fat could also contribute to metabolic imbalance by switching the fiber type towards less oxidative (less insulin sensitive) fibers, by lack of antiinflammatory and insulin-sensitizing myokine production as well as by chronic inflammation associated with mitochondrial stress and stress of endoplasmic reticulum (Fig. 10.). Our environment greatly modifies our metabolic health by means of dietary influences and exercise activity which together with pathologies associated with hyperlipidemia, chronic systemic hypoxia and tissue inflammation determines adipose tissue and skeletal muscle metabolic and secretory phenotype and subsequently our metabolic health.

It is generally accepted that regular physical activity prevents metabolic and cardiovascular disease development, and supports healthy aging. Skeletal muscle has been shown to produce and secrete several bioactive factors (hormones) termed "myokines". Different spectra of myokines originating from either active "trained" or inactive "sedentary" skeletal muscles elicit distinct adaptive changes in immune system, metabolic balance and processes of cellular growth and differentiation in order to maintain the whole body homeostasis. This requires extensive communication of skeletal muscle with many different cells and organs but the nature of mechanisms that tie muscle activity to metabolic health is not completely understood. It seems to be essential (i) to identify myokines differentially expressed and secreted from muscle cells derived from healthy and obese individuals, and individuals with type 2 diabetes; to (ii) determine basic principles of the muscle cross-communication with adipocytes (differentiation) and endothelial cells (angiogenesis) in fostering tissue plasticity necessary for adaptation to obesity and type 2 diabetes; and (iii) to discover novel myokines and to investigate their physiological significance in cell culture models and *in vivo* in genetically modified animal models as well as in humans. Myokines may be involved in mediating the health beneficial effects of exercise and play important roles in the protection against chronic diseases associated with low-grade inflammation, insulin resistance, hyperlipidemia, such as cardiovascular disease, type-2-diabetes, and cancer. Extension of the knowledge on the mechanisms whereby regular exercise offers protection against chronic diseases in combination with clinical research serves as a foundation for the development of public health guidelines with regard to exercise. Moreover, identification of new myokines and understanding basic principles and mechanisms of their action will potentially provide pharmacological targets for the treatment of metabolic and cardiovascular disorders.

### **6. Acknowledgement**

158 Dyslipidemia - From Prevention to Treatment

Fig. 9. The free radical theory of aging posits that a senescent phenotype is induced by accumulation of oxidative damage resulting from reactive oxygen species. Exercise and caloric restriction (CR) are two interventions that induce mitochondrial biogenesis through PGC-1α. Although exercise and CR increase average life expectancy by protecting against age-related comorbidities, only CR has been shown to increase maximal life span; an effect

metabolic health

**skeletal muscle in OBESITY** 




& mitochondria

that seems to require the activation of sirtuins (Lanza & Nair 2010).


secretion

& activation

& mitochondria



**adipose tissue in OBESITY** 


Fig. 10. Determinants of metabolic health and disease (Ukropec et al. 2008)

Ability of tissues to adapt morphologically and functionally to different physiological situations determines the overall metabolic health. Increased adipose tissue mass but mainly adipocyte lipid overload is responsible for the "pathogenic" adipose tissue phenotype. This

metabolic disease

**5. Conclusion** 

We would like to express our cordial gratitude to everybody who contributed to this work. There is too many people to thank. Above all we would like to acknowledge our parents and our wonderfull children Kiki and Jakub, our inspiration in everyday life. We would also like to thank the funding agencies: APVV grant agency (APVV 0122-06), European Foundation to Study Diabetes (EFSD New Horizons Collaborative Research Grant) and the 7th FP EC 2007-2.1.1-6. grant entitled "LipidomicNET" for their generous support.

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**9** 

*1USA 2Greece* 

**Pleiotropic Functions of HDL Lead to** 

Vassilis Zannis1,2, Andreas Kateifides1,2, Panagiotis Fotakis1,2,

*1Molecular Genetics, Boston University School of Medicine Boston, MA,* 

High density lipoprotein (HDL) is a macromolecular complex of proteins and lipids that is produced primarily by the liver through a complex pathway that requires initially the functions of apolipoprotein A-I (apoA-I), ATP binding cassette transporter A1 (ABCA1) and lecithin:cholesterol acetyl transferase (LCAT) (Zannis et al., 2006b). Following synthesis, HDL affects the functions of the arterial wall cells through signaling mechanisms mediated by scavenger receptor class B type-I (SR-BI) and other cell surface proteins. The impetus for studying HDL has been the inverse correlation that exists between plasma HDL levels and the risk for coronary artery disease (CAD) (Gordon et al., 1989). HDL promotes cholesterol efflux (Gu et al., 2000; Nakamura et al., 2004), prevents oxidation of low density lipoprotein (LDL) (Navab et al., 2000a; Navab et al., 2000b), inhibits expression of proinflammatory cytokines by macrophages (Okura et al., 2010) as well as expression of adhesion molecules by endothelial cells (Cockerill et al., 1995; Nicholls et al,. 2005b). HDL inhibits cell apoptosis (Nofer et al., 2001) and promotes endothelial cell proliferation and migration (Seetharam et al., 2006). HDL stimulates release of nitric oxide (NO) from endothelial cells thus promoting vasodilation (Mineo et al., 2003). HDL also inhibits platelet aggregation and thrombosis (Dole et al., 2008) and has antibacterial, antiparasitic and antiviral activities (Parker et al., 1995; Singh et al., 1999; Vanhollebeke and Pays, 2010). Due to these properties HDL is thought to protect the endothelium and inhibit several steps in the cascade of events that lead to the

This review focuses on two important aspects of contemporary HDL research. The first part considers briefly the structure of apoA-I and HDL and the key proteins that participate in the pathway of the biogenesis of HDL as well as clinical phenotypes associated with HDL abnormalities. The second part considers various physiological functions of HDL and apoA-I and the protective role of HDL against atherosclerosis and

pathogenesis of atherosclerosis and various other human diseases.

**1. Introduction** 

other diseases.

**Protection from Atherosclerosis** 

**and Other Diseases** 

Eleni Zanni1 and Dimitris Kardassis2

*2University of Crete Medical School, Greece,* 

