**1. Introduction**

410 Dyslipidemia - From Prevention to Treatment

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Benign prostatic hyperplasia (BPH) is a common melody of the aging men characterized by noncancerous enlargement of the prostate gland and is often associated with lower urinary tract symptoms (LUTS) (Berry et al., 1984). Approximately, 60 percent of men aged over 50 years have histological evidence of BPH and, after the age of 70, the proportion increases to 80 percent (Berry et al., 1984). It is a chronic, progressive and highly prevalent disease, clinically manifests as LUTS, posing a socioeconomic burden to the patients (Saigal and Joyce, 2005). Recently, Stranne et al., reported that one-third of the Swedish male population aged over 50 years have LUTS, which is often associated with BPH (Stranne et al., 2009). BPH is rarely fatal, but affects the quality of life, and if left untreated, serious lifethreatening complications may arise. Prostatic growth and development are governed by the genetic (Sanda et al., 1994), hormonal (Marker et al., 2003) and dietary factors (Bravi et al., 2006). Although, its etiology is not well understood, several theories have been proposed to explain the pathogenesis of BPH (Alberto et al., 2009; Bosch, 1991; Srinivasan et al., 1995). Augmented steroidal signaling and mesenchymal-epithelial interactions are required for the normal as well as pathological growth of the prostate gland (Marker et al., 2003). However, current literature indicates that apart from steroids, peptides and lipids are also playing a crucial role in the pathogenesis of BPH (Cai et al., 2001; Culig et al., 1996; Escobar et al., 2009; Kaplan-Lefko et al., 2008; Rahman et al., 2007; Rick et al., 2011; Story, 1995; Vikram and Jena, 2011a; Vikram et al., 2010c). Even if the effects of peptides and lipids on the growth of the gland is milder as compared to that of steroids, chronic change in their levels either due to dietary habit or genetic predispositions can significantly contribute to the initiation and/or progression of the disease over a period of time. Existing clinical/epidemiological and preclinical studies provide convincing evidence for the association between insulinresistance, metabolic disorder and type 2 diabetes with the BPH (Francisco and Francois, 2010; Vikram et al., 2010a; Wang and Olumi, 2011). Previous experimental studies in our laboratory suggested that insulin-resistance associated secondary rise in the plasma insulin level plays a central role in the prostatic enlargement (Vikram and Jena, 2011b; Vikram et al., 2010a; b; 2011a; Vikram et al., 2010c; Vikram et al., 2011b). Other peptides such as insulinlike growth factor-I (IGF-I), IGF-I binding proteins (IGFBPs), growth hormone (GH), transforming growth factor-β (TGF-β) family proteins are reported to have important

Lipids in the Pathogenesis of Benign Prostatic Hyperplasia: Emerging Connections 413

increased from 2:1 to 25:1 (Simopoulos, 1999), and animal fat is a major source of ω-6-FAs which has been found to be associated with the higher risk of LUTS and BPH (Maserejian et al., 2009; Suzuki et al., 2002). Considering the rise in the incidence of LUTS/BPH in the obese and insulin-resistant individuals, it becomes increasingly important to understand the

Limited information is available on the direct role of fatty acids (FAs) in the growth of normal and benign prostatic cells, as most of the studies have been conducted on the prostate cancer cell lines. However, cancer cell lines studies have indicative value for the potential effects of these FAs, as like prostate cancer, BPH is also associated with the pathological increase in the cell proliferation. A recent report indicating dominant uptake of FAs by the prostate cells [non-malignant (RWPE-1) as well as malignant (LnCaP and PC-3)] suggests their important role in the growth and development of the gland (Liu et al., 2010). Pandalai et al., reported growth promoting effects of ω-6-FAs on the rat non metastatic epithelial cell lines (EPYP1 & EPYP2), rat metastatic cell line (Met-Ly-Lu), and human metastatic prostate cancer cells (PC-3, LnCaP & TSU) (Pandalai et al., 1996). Arachidonic acid, a ω-6-FA treatment led to accelerated growth of the PC-3 cells in-vitro (Ghosh and Myers, 1997). Further, Rose et al., reported concentration-dependent stimulation of PC-3 cells by the linolenic acid (ω-6-FA) and inhibition with the eicosapentanoic acid and docosahexanoic acid (ω-3-FAs) (Rose and Connolly, 1991). Further, long term eicosapentanoic acid treatment has been found to inhibit the metastatic activities of the PC-3 cells (Rose and Connolly, 1991). Recently, we investigated the effects of the serum of highfat diet-fed (saturated animal fat-lard) rats on the growth of PC-3 cells, and a significant acceleration in the growth was observed (Vikram and Jena, 2011a). The serum characteristics of these rats indicated a rise in the glucose, triglyceride, cholesterol and insulin levels. Although, rise in the insulin level appears to be the primary cause for the accelerated growth of the cells owing to the mitogenic effects of the hormone, the possibility of direct growth promoting effects of lipids cannot be denied. Taken together, these studies suggest that at least ω-6-FAs have a growth stimulating effects on the prostatic cells, and thus

The study by Cai et al., provided first evidence for the prostatic growth promoting effects of dietary fat in rats (Cai et al., 2001). Similarly, Rahman et al., observed enlargement of the ventral prostate and increased expression of alpha-adrenergic receptors in the hyperlipidemic rats (Rahman et al., 2007). Further, inclusion of the saturated animal fat (lard) in the diet induced prostatic enlargement and changed the expression of androgen receptor and peroxysome proliferator activated receptor γ (PPARγ) (Escobar et al., 2009). Polyunsaturated FAs are ligands for the PPARγ, which is involved in the regulation of cell differentiation and proliferation (Morales-Garcia et al., 2011; Parast et al., 2009), and therefore appears to represent a possible link between diet and prostatic growth (Escobar et al., 2009). Prostatic atrophy and increased apoptosis in the hypoinsulinemic rats (induced by selective β-cell toxins, either streptozotocin or alloxan) further supports the view that insulin plays a central role in the prostatic growth and development (Arcolino et al., 2010; Ikeda et al., 2000; Suthagar et al., 2009; Vikram et al., 2011b; Vikram et al., 2008; Yono et al., 2008;

role of lipids in the pathogenesis of disease.

**4.1 Evidence from in-vitro experiments** 

represent a potential risk factor for BPH.

**4.2 Evidence from in-vivo experiments** 

implications in the prostatic growth (Culig et al., 1996; Ikeda et al., 2000; Rick et al., 2011; Vikram et al., 2010c). However, information on the role of lipids in the prostatic growth is scarce and there is a need of further research in this area. Nevertheless, existing in-vitro, invivo and clinical/epidemiological studies suggests that apart from contributing to the development of insulin-resistance and secondary hyperinsulinemia, lipids has a direct role in the normal prostatic growth and pathogenesis of the BPH.
