**4. Growth hormone**

#### **4.1. Growth hormone and growth hormone receptors**

Growth hormone (GH) is secreted by the somatotroph cells of the anterior pituitary gland under neural, hormonal and metabolic control. GH regulates postnatal growth, as well as lipid, glucose and energy metabolism. The molecular mechanism of GH action is relatively complicated. It affects metabolism through direct or indirect action via insulin-like growth factor-1 (IGF-1) or antagonism of insulin action. GH receptor (GHR) is a member of the cytokine receptor superfamily. Upon binding to GH, GHR activates the cytoplasmic tyrosine kinase Janus kinase 2 (Jak2) and then recruits members of the signal transducer and activator of transcription (STAT) family of transcription factors. Phosphorylated STATs translocate into the nucleus and modulate the transcription of multiple target genes, including IGF-1, ALS and suppressor of cytokine signaling (SOCS) [36]. In addition to the Jak2/STAT signaling pathway, GHR can activate the Src tyrosine kinase signaling pathway and cross talk with insulin and IGF-1 signaling pathways.

GHR is present in the liver and critical for the hepatic lipid metabolism. Laron dwarfism is a disorder characterized by an insensitivity to GH due to a genetic mutation of GHR. These male patients manifest NAFLD in adults [47]. Liver-specific deletion of GHR in mice leads to increased circulating free fatty acids and fatty liver as a result of increased synthesis and decreased efflux of triglyceride [48]. Binding of GH to GHR activates JAK2-STAT5 signaling pathway and modulates a number of target genes. Among these, altered expression of CD36, PPARγ and PGC1α/β, along with fatty acid synthase, lipoprotein lipase and very-low-density lipoprotein receptor (VLDLr) contributes to the hepatic lipid metabolism process [49, 50]. All these findings suggest that hepatic GH signaling is essential for the regulation of intrahepatic

Hormonal Regulation of Cholesterol Homeostasis http://dx.doi.org/10.5772/intechopen.76375 25

Glucagon is a 29-aa peptide hormone secreted from the pancreatic islet alpha cells in response to low glucose. It is a well-known counter-regulatory hormone to insulin, mainly stimulating hepatic glucose production by increasing glycogenolysis and gluconeogenesis and concurrently inhibiting glycogen synthesis. Glucagon also affects hepatic cholesterol metabolism. The relationship between glucagon and cholesterol has been investigated since the 1950s [51]. The portacaval shunt surgery in a 6-year-old girl with the homozygous form of familial hypercholesterolemia disorder has been reported to significantly reduce LDL and cholesterol synthesis 5 months after surgery. This alteration is associated with a marked elevation of bile acids and the glucagon level, indicating that glucagon may improve hepatic lipid metabolism [52]. In the animal study, infusion of glucagon into the hyperlipidemic rat reduces circulating VLDL apoprotein and serum TG levels. It is due to the inhibition of incorporating amino acid into the apoprotein by glucagon [53]. Chronic glucagon administration in rats significantly reduces serum cholesterol and triglyceride levels but not in the liver. The internal secretion of cholesterol and cholesterol transformation into bile acids measured by an isotope balance method are strikingly increased, suggesting that glucagon stimulates cholesterol turnover rate [54]. Studies by Rudling et al. have found that injection of glucagon increases LDL binding to the LDLr in a dose-dependent manner and concomitantly decreases cholesterol and apoB/E in LDL and large HDL particles in rats. Moreover, the induction of LDLr by glucagon is not due to increased mRNA levels, indicating a novel posttranscriptional regulatory mechanism present in the liver [55]. In humans, glucagon administration represses cholesterol 7α-hydroxylase (CYP7A1) mRNA expression by increasing the PKA phosphorylation of HNF4a and reducing

its ability to bind with the CYP7A1 gene, thus inhibiting bile acid synthesis [56].

Glucagon receptor, encoded by the GCGR gene, is a seven-transmembrane protein and belongs to the class II guanine nucleotide-binding protein (G protein)-coupled receptor superfamily. They are abundantly expressed in the liver and kidney. In the liver, glucagon receptors are mainly located in hepatocytes, with a small number expressed on the surface of Kupffer cells [57]. Mice with a null mutation of the glucagon receptor (*Gcgr−/−*) display low blood glucose and markedly elevated the plasma LDL level. Serum total cholesterol and HDL are not significantly changed in *Gcgr−/−* mice [58]. *Gcgr−/−* mice are more prone to develop

lipid and cholesterol metabolism.

**5. Glucagon**

#### **4.2. Role of GH in cholesterol and lipid metabolism**

There exists a negative relationship between obesity and GH. Enormous evidence supports that GH alters lipid metabolism. Clinical studies have shown a significant association between lower serum GH levels and non-alcoholic fatty liver disease (NAFLD). Hypopituitary patients with GH deficiency are more prone to NAFLD than control subjects [37–39]. GH supplementation has been shown to improve the NAFLD and the metabolic dysfunction [40, 41]. In rodent studies, high-fat diet feeding and obesity suppress pulsatile GH secretion [42]. In turn, chronic GH treatment ameliorates hepatic lipid peroxidation and improves lipid metabolism in high-fat diet-fed rats [43].

Hypophysectomy is a surgery process in which the pituitary gland (hypophysis) is removed, leading to an impairment of GH secretion. This model is used for investigating the GH function in animals under pathophysiology conditions. Increase of hepatic LDLr and hypocholesterolemia induced by estrogens is completely attenuated in hypophysectomized rats. Only GH supplementation is able to restore this effect of hypophysectomy. Further, GH treatment on the gallstone patients stimulates the expression of hepatic LDLr by twofold, leading to subsequent decrease in serum cholesterol by 25%. This study indicates that GH secretion is critical for the control of plasma LDL levels in humans [44]. GH is also important for the synthesis of bile acids by maintaining the normal activity of cholesterol 7α-hydroxylase. Hypophysectomized rats show significantly reduced activities of HMG-CoA reductase and cholesterol 7α-hydroxylase and hence an inhibition of cholesterol and bile acid biosynthesis. GH substitution restores the enzymatic activity of 7α-hydroxylase and increases the fecal excretion of bile acids [45]. Treatment of LDLr-deficient mice with GH reduces their elevated plasma cholesterol and triglyceride levels by stimulating the activities of HMG-CoA reductase and cholesterol 7α-hydroxylase [46]. GH thus regulates plasma lipoprotein levels and bile acid metabolism by altering hepatic LDLr expression and the enzymatic activity of cholesterol 7α-hydroxylase, respectively.

GHR is present in the liver and critical for the hepatic lipid metabolism. Laron dwarfism is a disorder characterized by an insensitivity to GH due to a genetic mutation of GHR. These male patients manifest NAFLD in adults [47]. Liver-specific deletion of GHR in mice leads to increased circulating free fatty acids and fatty liver as a result of increased synthesis and decreased efflux of triglyceride [48]. Binding of GH to GHR activates JAK2-STAT5 signaling pathway and modulates a number of target genes. Among these, altered expression of CD36, PPARγ and PGC1α/β, along with fatty acid synthase, lipoprotein lipase and very-low-density lipoprotein receptor (VLDLr) contributes to the hepatic lipid metabolism process [49, 50]. All these findings suggest that hepatic GH signaling is essential for the regulation of intrahepatic lipid and cholesterol metabolism.
