**3. Sex hormones**

It is well recognized that premenopausal females have better lipid profiles than males and are more protected from hypercholesterolemia-related diseases, such as cardiovascular diseases. Lipid screening has found that premenopausal women are associated with a lower level of LDL cholesterol and a higher level of HDL cholesterol. After menopause, the gender difference of lipid profiles disappears, and women even have higher-level LDL compared to age-matched men [17]. Estrogen replacement therapy would improve lipoprotein profiles in postmenopausal women [18]. Sex hormones, especially estrogen, account for the gender difference of cholesterol profiles.

which mediates the efflux of cholesterol to the HDL particles, leading to the subsequent increase in the HDL cholesterol level [26]. Estrogens thus play an important role in the modulation of the total cholesterol level by reducing LDL and concurrently increasing HDL.

Hormonal Regulation of Cholesterol Homeostasis http://dx.doi.org/10.5772/intechopen.76375 23

The beneficial role of estrogens on cholesterol metabolism is mediated through nuclear and extranuclear ER-α and ER-β, as well as GPER. Genetic deletion of ER-α in mice results in upregulation of the genes involved in hepatic lipid biosynthesis and downregulation of the genes involved in lipid transport, indicating that estrogens act via ER-α to regulate lipid metabolism [27]. ER-α KO and ER-α/β double KO mice showed increased serum cholesterol and smaller LDL particles, but not in ER-β single KO mice [28]. Therefore, ER-α plays a more prominent role than ER-β. The roles of GPER in the regulation of metabolism are only beginning to emerge, which gains more attentions. GPER knockout mice exhibit impaired cholesterol homeostasis manifesting significantly a higher LDL level but a normal HDL level, suggesting that GPER mainly regulates LDL metabolism [29]. And, human individuals with a hypofunctional GPER P16L allele are associated with elevated plasma LDL. In vitro study shows that activation of GPER by the agonist upregulates hepatic LDLr expression [30]. The role of GPER signaling in cholesterol or metabolic control remains unclear and needs more further investigations [31]. In summary, estrogens protect

against increases in the plasma cholesterol level mainly by activating ER-α and GPER.

subsequent regulation of the target genes' transcription.

the cholesterol homeostasis in the liver.

The human androgens include dehydroepiandrosterone, androstenedione, testosterone and dihydrotestosterone (DHT). Testosterone can be converted to DHT via 5α-reductase. Testosterones and DHT are active androgens, because they are the only androgens capable of binding to androgen receptors (ARs) to exert biological functions. AR is mainly expressed in the prostate, skeletal muscle, liver and central nervous system (CNS). Like ERs, AR is a member of the steroid and nuclear receptor superfamily. Ligand binding induces a conformation change of AR, leading to recruitment of cofactor proteins and transcriptional machinery and

The effect of androgen on cholesterol is still not conclusive. Clinical studies show that androgen deficiency, such as in old men, is associated with increased risks of dyslipidemia, higher serum cholesterol and LDL levels [32]. Another study has found that AR antagonists might be useful in the treatment of obesity in men [33]. In the animal studies, dihydrotestosterone (DHT) treatment in castrated obese mice decreases LDL secretion and increases the expression of hepatic scavenger receptor class B member 1 (SR-1B) which is important in regulating cholesterol uptake from HDL. It also decreases the enzyme cholesterol 7α-hydroxylase which participates in bile formation and cholesterol removal. In another study using an orchidectomized Sprague–Dawley (SD) rat model, DHT treatment causes decreased lipid accumulation and cholesterol synthesis by increasing expression of carnitine palmitoyl transferase 1 and phosphorylation of HMG-CoA reductase via an AR-mediated pathway [34]. However, this finding in animals contradicts a clinical study showing that a single dose of testosterone injection increases the total cholesterol level by 15% through stimulating the hepatic expression of HMG-CoA reductase [35]. These contradictory results indicate a complex role of androgen on

**3.3. Androgens**

#### **3.1. Estrogen and estrogen receptors**

The predominant and most important biologically relevant form of estrogen is 17β-estradiol (E2). Both women and men produce E2 through aromatization of androgen. In premenopausal women, estrogen is mainly synthesized in the ovaries. While in postmenopausal women and men, it is primarily converted from testosterone by aromatase (encoded by CYP19 gene) in extragonadal tissues such as adipose tissue, adrenal glands, bones, etc. [19]. There are at least three types of estrogen receptors, ER-, ER- and membrane-bound receptor G protein-coupled ER (GPER, also known as GPR 30). ER-α and ER-β are the classic estrogen receptors and are mainly expressed in the cytosol. Upon estrogen binding, ER-α and ER-β form homo- or heterodimers and bind to estrogen response element (ERE) in the downstream target genes, to initiate or suppress the transcriptional activity. The GPER and membrane-associated ER-α and ER-β variants are expressed in the plasma membrane. They mainly exert actions via non-genomic signaling. This membrane-initiated signaling involves protein kinase A (PKA), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK)/extracellular signalregulated protein kinase (ERK) signaling pathways [20–22].

#### **3.2. Role of estrogens in cholesterol homeostasis**

The influence and mechanism of estrogens on cholesterol metabolism have been investigated for a long time. Studies by Cypriani et al. in 1988 demonstrated that estrogens induced HMG-CoA reductase and subsequent cholesterol synthesis in breast cancer cell line [4]. Later, it was found that HMG-CoA reductase gene promoter contains an estrogen-responsive element-like sequence at position-93 (termed Red-ERE). And, estrogen induction of HMG-CoA reductase gene is dependent on the Red-ERE. The induction activity of estrogens occurs in the breast cancer cells but not in hepatic cells, indicating differential regulation of HMG-CoA reductase by estrogens in a tissue-specific manner [23]. Aromatase is an enzyme responsible for the key step in the biosynthesis of estrogens. Aromatase knockout (ArKO) mice display increased intra-abdominal adipose tissue and lipid droplet accumulation in the liver. Total cholesterol and LDL are also elevated in these transgenes [24]. Supplement of estrogens in both ArKO mice and rats with ovariectomy (OVX) normalizes LDL and total cholesterol levels, confirming the important role of estrogens in the lipid homeostasis in both males and females [25]. Hormone replacement therapy (HRT) increases the expression of leucocyte ABCA1 gene, which mediates the efflux of cholesterol to the HDL particles, leading to the subsequent increase in the HDL cholesterol level [26]. Estrogens thus play an important role in the modulation of the total cholesterol level by reducing LDL and concurrently increasing HDL.

The beneficial role of estrogens on cholesterol metabolism is mediated through nuclear and extranuclear ER-α and ER-β, as well as GPER. Genetic deletion of ER-α in mice results in upregulation of the genes involved in hepatic lipid biosynthesis and downregulation of the genes involved in lipid transport, indicating that estrogens act via ER-α to regulate lipid metabolism [27]. ER-α KO and ER-α/β double KO mice showed increased serum cholesterol and smaller LDL particles, but not in ER-β single KO mice [28]. Therefore, ER-α plays a more prominent role than ER-β. The roles of GPER in the regulation of metabolism are only beginning to emerge, which gains more attentions. GPER knockout mice exhibit impaired cholesterol homeostasis manifesting significantly a higher LDL level but a normal HDL level, suggesting that GPER mainly regulates LDL metabolism [29]. And, human individuals with a hypofunctional GPER P16L allele are associated with elevated plasma LDL. In vitro study shows that activation of GPER by the agonist upregulates hepatic LDLr expression [30]. The role of GPER signaling in cholesterol or metabolic control remains unclear and needs more further investigations [31]. In summary, estrogens protect against increases in the plasma cholesterol level mainly by activating ER-α and GPER.

#### **3.3. Androgens**

**3. Sex hormones**

22 Cholesterol - Good, Bad and the Heart

ference of cholesterol profiles.

**3.1. Estrogen and estrogen receptors**

regulated protein kinase (ERK) signaling pathways [20–22].

**3.2. Role of estrogens in cholesterol homeostasis**

It is well recognized that premenopausal females have better lipid profiles than males and are more protected from hypercholesterolemia-related diseases, such as cardiovascular diseases. Lipid screening has found that premenopausal women are associated with a lower level of LDL cholesterol and a higher level of HDL cholesterol. After menopause, the gender difference of lipid profiles disappears, and women even have higher-level LDL compared to age-matched men [17]. Estrogen replacement therapy would improve lipoprotein profiles in postmenopausal women [18]. Sex hormones, especially estrogen, account for the gender dif-

The predominant and most important biologically relevant form of estrogen is 17β-estradiol (E2). Both women and men produce E2 through aromatization of androgen. In premenopausal women, estrogen is mainly synthesized in the ovaries. While in postmenopausal women and men, it is primarily converted from testosterone by aromatase (encoded by CYP19 gene) in extragonadal tissues such as adipose tissue, adrenal glands, bones, etc. [19]. There are at least three types of estrogen receptors, ER-, ER- and membrane-bound receptor G protein-coupled ER (GPER, also known as GPR 30). ER-α and ER-β are the classic estrogen receptors and are mainly expressed in the cytosol. Upon estrogen binding, ER-α and ER-β form homo- or heterodimers and bind to estrogen response element (ERE) in the downstream target genes, to initiate or suppress the transcriptional activity. The GPER and membrane-associated ER-α and ER-β variants are expressed in the plasma membrane. They mainly exert actions via non-genomic signaling. This membrane-initiated signaling involves protein kinase A (PKA), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK)/extracellular signal-

The influence and mechanism of estrogens on cholesterol metabolism have been investigated for a long time. Studies by Cypriani et al. in 1988 demonstrated that estrogens induced HMG-CoA reductase and subsequent cholesterol synthesis in breast cancer cell line [4]. Later, it was found that HMG-CoA reductase gene promoter contains an estrogen-responsive element-like sequence at position-93 (termed Red-ERE). And, estrogen induction of HMG-CoA reductase gene is dependent on the Red-ERE. The induction activity of estrogens occurs in the breast cancer cells but not in hepatic cells, indicating differential regulation of HMG-CoA reductase by estrogens in a tissue-specific manner [23]. Aromatase is an enzyme responsible for the key step in the biosynthesis of estrogens. Aromatase knockout (ArKO) mice display increased intra-abdominal adipose tissue and lipid droplet accumulation in the liver. Total cholesterol and LDL are also elevated in these transgenes [24]. Supplement of estrogens in both ArKO mice and rats with ovariectomy (OVX) normalizes LDL and total cholesterol levels, confirming the important role of estrogens in the lipid homeostasis in both males and females [25]. Hormone replacement therapy (HRT) increases the expression of leucocyte ABCA1 gene, The human androgens include dehydroepiandrosterone, androstenedione, testosterone and dihydrotestosterone (DHT). Testosterone can be converted to DHT via 5α-reductase. Testosterones and DHT are active androgens, because they are the only androgens capable of binding to androgen receptors (ARs) to exert biological functions. AR is mainly expressed in the prostate, skeletal muscle, liver and central nervous system (CNS). Like ERs, AR is a member of the steroid and nuclear receptor superfamily. Ligand binding induces a conformation change of AR, leading to recruitment of cofactor proteins and transcriptional machinery and subsequent regulation of the target genes' transcription.

The effect of androgen on cholesterol is still not conclusive. Clinical studies show that androgen deficiency, such as in old men, is associated with increased risks of dyslipidemia, higher serum cholesterol and LDL levels [32]. Another study has found that AR antagonists might be useful in the treatment of obesity in men [33]. In the animal studies, dihydrotestosterone (DHT) treatment in castrated obese mice decreases LDL secretion and increases the expression of hepatic scavenger receptor class B member 1 (SR-1B) which is important in regulating cholesterol uptake from HDL. It also decreases the enzyme cholesterol 7α-hydroxylase which participates in bile formation and cholesterol removal. In another study using an orchidectomized Sprague–Dawley (SD) rat model, DHT treatment causes decreased lipid accumulation and cholesterol synthesis by increasing expression of carnitine palmitoyl transferase 1 and phosphorylation of HMG-CoA reductase via an AR-mediated pathway [34]. However, this finding in animals contradicts a clinical study showing that a single dose of testosterone injection increases the total cholesterol level by 15% through stimulating the hepatic expression of HMG-CoA reductase [35]. These contradictory results indicate a complex role of androgen on the cholesterol homeostasis in the liver.
