**2.1 What is dehydroepiandrosterone?**

DHEA, and its interchangeable sulfated form, DHEA-S (Fig 2.), are the most abundant circulating steroid hormone in healthy individuals. They are produced from cholesterol by the zona reticularis of the adrenal cortex. DHEA is produced from cholesterol through two cytochrome P450 enzymes. Cholesterol is converted to pregnenolone by the enzyme P450 scc (side chain cleavage); then another enzyme, CYP17A1, converts pregnenolone to 17α-Hydroxypregnenolone and then to DHEA. (Fig 3) (Arlt, 2004). DHEA is made primarily in the adrenal glands (which also produce about 150 other hormones) and released into the blood. In different organs it is converted into a variety of more commonly known steroid

Fig. 1. The distribution of age and gender in patients with biopsy-proven NAFLD (n=619) according to fibrosis stage (stage 0-2 or stage 3-4) in Japan Study Group of NAFLD (JSG-

Endocrine hormones control cell metabolism and the distribution of body fat and, therefore, may contribute to the development of NAFLD/ NASH. Dehydroepiandrosterone (DHEA), and its interchangeable sulfated form, DHEA sulfate (DHEA-S), is the most abundant circulating steroid hormone and is produced primarily by the zona reticularis of the adrenal cortex in response to adrenocorticotropic hormone. DHEA has been known to have a variety of functions, including anti-oxidative stress, decreasing insulin resistance, antiatherosclerosis, and anti-osteoporosis (Baulieu et al. 2000). DHEA-S concentration is independently and inversely related to death from any cause and death from cardiovascular disease in men over age 50. It has been postulated that DHEA and DHEA-S may be discriminators of life expectancy and aging (Phillips et al. 2010). In this chapter, we describe

DHEA, and its interchangeable sulfated form, DHEA-S (Fig 2.), are the most abundant circulating steroid hormone in healthy individuals. They are produced from cholesterol by the zona reticularis of the adrenal cortex. DHEA is produced from cholesterol through two cytochrome P450 enzymes. Cholesterol is converted to pregnenolone by the enzyme P450 scc (side chain cleavage); then another enzyme, CYP17A1, converts pregnenolone to 17α-Hydroxypregnenolone and then to DHEA. (Fig 3) (Arlt, 2004). DHEA is made primarily in the adrenal glands (which also produce about 150 other hormones) and released into the blood. In different organs it is converted into a variety of more commonly known steroid

here the role of DHEA or DHEA-S in the pathogenesis or treatment of NAFLD.

NAFLD), including nine hepatology centers throughout Japan.

**2. NAFLD and dehydroepiandrosterone** 

**2.1 What is dehydroepiandrosterone?** 

hormones, including androstenedione, testosterone, and estrogen. DHEA and DHEA-S levels peak at approximately age 25 years and decrease progressively thereafter, falling to 5% of peak levels by the ninth decade. DHEA is a potential mediator of ROS synthesis (Bednarek-Tupikowska et al., 2000) and has also been reported to augment insulin sensitivity (Lasco et al., 2001, Jakubowicz et al., 1995, Kawano, 2000, Dhatariya et al., 2005) and peroxisome proliferator activation. (Poynter & Daynes, 1998, Peters et al., 1996), a transcription factor that regulates lipid metabolism, and procollagen type I, collagen precursor that has been associated with hepatic fibrosis of NASH. Both cross-sectional and longitudinal data have clearly indicated that serum concentrations of DHES-S decrease with age. Advocates of DHEA recommend it to prevent the effects of aging.

Fig. 2. DHEA and DHEA-S

Fig. 3. Synthesis pathway of DHEA and DHEA-S

Dehydroepiandrosterone in Nonalcoholic Fatty Liver Disease 101

similar between those with NAFLD and without. (Kauffman et al., 2010). According to a crosssectional population-based study derived from data of 1912 men, however, the highest risk of hepatic steatosis was found in subjects with the highest serum DHEA-S levels (Völzke H et al., 2010). DHEA and DHEAS levels of post menopausal women with fatty liver were greater than those of post menopausal women with normal histology. (Saruç et al., 2003) These results are contrast to our study. Discrepancies between these studies and ours might be explained by

Only in our NAFLD patients, NASH patients had lower levels of serum DHEA-S levels compared to non-NASH patients (Fig 4). Serum DHEA levels were negative correlated with age in males and females (Fig 5). A " dose effect " of lower DHEA-S and advanced fibrosis was observed, with a mean DHEA-S of 170.4±129.2, 137.6±110.5, 96.2±79.3, 61.2±46.3, and

differences in the selection of subjects, sex, size of the study populations and ethnicity.

Fig. 5. The relationship between serum DHEA-S levels and age in NAFLD patients

Fig. 4. Serum DHEA levels in biopsy-proven NAFLD.
