**5. Emerging mechanistic connections**

### **5.1 Autotaxin-lysophosphatidic acid pathway**

Lysophophatidic acid (LPA) is a small water soluble phospholipid, which binds to its Gprotein coupled receptors and activates several downstream signaling pathways (Berdichevets et al., 2010; Rancoule et al., 2011). It is primarily produced by the activity of the phospholipase autotaxin (ATX) (Van Meeteren and Moolenaar, 2007). Excessive fat intake is associated with adiposity, development of insulin-resistance and obesity, and these conditions are known to increase the expression of ATX, and therefore the LPA levels (Ferry et al., 2003). Recent study indicating the expression of LPA-related molecules in the prostate (Zeng et al., 2009) suggests that LPA might have an important role in the normal prostatic growth and pathogenesis of the BPH (Sakamoto et al., 2004). Kulkarni et al., proposed ATX-LPA axis as a possible link between excessive dietary fat intake and prostatic hyperplasia (Kulkarni and Getzenberg, 2009). LPA is involved in the inflammatory responses and experimental studies indicating increased oxidative stress and NF-kB activation in the ventral prostate of high-fat diet-fed rodents (Sekine et al., 2011; Vykhovanets et al., 2011), which are known to develop prostatic enlargement (Vikram et al., 2010b; 2011a; Vikram et al., 2010c) supports the hypothesis. Further, clinical studies indicate that systemic inflammation or lower level of soluble receptors that bind to the inflammatory cytokines increase the BPH risk (Schenk et al., 2010). The pharmacological inhibitors of ATX such as S32826 (Ferry et al., 2008) and ongoing efforts of medicinal chemists (North et al., 2010; North et al., 2009; Parrill and Baker, 2010) in this direction might provide an answer to therapeutic management of the BPH.

Lipids in the Pathogenesis of Benign Prostatic Hyperplasia: Emerging Connections 417

Androgen deprivation leads to rapid apoptosis of the luminal secretory cells and atrophy of the prostate gland (Ikeda et al., 2000; Vikram et al., 2010c; Vikram et al., 2008). However, with the re-administration of the androgens prostate regains its normal size, and is capable of more than 15 rounds of the regression / regeneration cycle (Wang et al., 2009). Further, administration of either estrogen or dihydrotestosterone leads to hyperproliferation and induction of prostatic hyperplasia in the experimental animals. These simple experiments highlights the crucial role of steroidal hormones in the growth and development of the gland. Aromatase is a CYP450 enzyme which irreversibly converts testosterone to the estradiol, and obesity is associated with increased aromatase activity (Subbaramaiah et al., 2011). Increased aromatase activity in the obese people may lead to rise in the estrogen/androgen ratio and hence the susceptibility for developing BPH. These aspects have been recently reviewed by Nicholson et al., and readers are encouraged to read the

Fig. 1. The IGF and insulin receptor signaling system. To avoid confusion, the binding affinity of the ligands and relative effects of hybrid receptors (metabolic and mitogenic) are not depicted in the figure. However, the IGF-IR/IR hybrid resembles IGF-IR homodimer and IR-A/IR-B resembles IR-A homodimers. Lipids are involved in nuclear signaling and can influence transcriptional regulation and thus growth and differentiation. IGF-I/II; insulin-like growth factor-I/II, IGF-IR; insulin-like growth factor-I receptor, IR-A/B; insuln

BPH is a highly prevalent condition of prostate in the aging men population. The worldwide increase in the prevalence of BPH has been thought to be associated with obesity and lifestyle changes such as excessive intake of fat-rich diet and physical inactivity. Considering

**5.4 Estrogen/androgen ratio** 

review (Nicholson and Ricke, 2011).

receptor isoform-A/B.

**6. Summary**
