GH-independent IGF-I action is essential to prevent the development of nonalcoholic steatohepatitis in a GH-deficient rat model

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Abstract

The progression to nonalcoholic steatohepatitis (NASH) from simple steatosis is associated with the mitochondrial dysfunction, enhanced oxidative stress, and inflammation. Recently, it has been reported that the prevalence of NAFLD (nonalcoholic fatty liver disease)/NASH is increased in patients with adult growth hormone deficiency (AGHD), suggesting that the deficiencies in GH and insulin-like growth factor (IGF-I) are involved in the development of NAFLD/NASH; however, the precise underlying mechanism remains to be elucidated. To clarify the mechanisms and the specific contribution of GH and IGF-I in these conditions, we examined the liver of a GH-deficient rat model, spontaneous dwarf rat (SDR) and the effect of GH and IGF-I administration. SDR showed steatosis and fibrosis in the liver in line with the phenotype observed in AGHD. Serum AST and ALT levels and triglyceride content in the liver were significantly increased in the SDR compared with the control. Intriguingly, the mitochondrial morphology in the SDR hepatocyte was impaired and the area was significantly decreased. Furthermore, oxidative stress in the SDR liver was enhanced. These changes were improved not only by GH but also by IGF-I administration, suggesting that GH-independent IGF-I action plays an essential role in the liver. In conclusion, we demonstrated that GH-deficient rat exhibits NASH and IGF-I plays an essential role to prevent the development of NASH. The improved mitochondrial function and reduced oxidative stress may contribute the effect of IGF-I in the liver.

Highlights

ā–ŗ Adult growth hormone deficiency has a high prevalence of nonalcoholic steatohepatitis (NASH). ā–ŗ However, the specific contribution of GH or IGF-I remains to be elucidated. ā–ŗ Not only GH but also IGF-I prevented the development of NASH in a GH-deficient rat model. ā–ŗ These results revealed a presence of GH-independent IGF-I action in the liver.

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. NAFLD refers to the accumulation of hepatic steatosis not due to excess alcohol consumption [1]. NAFLD includes both nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH). Histologically, NAFLD occurs as a spectrum from mild hepatic steatosis only, to NASH characterized by hepatocellular injury, inflammation, and fibrosis to cirrhosis. NASH is a serious disease because it is intractable and progressive. The progression to NASH is associated with multiple factors, but it generally consists of two steps; first, the insulin resistance in conjunction with an accumulation of fat in visceral adipose tissue and within hepatocytes; and second, the increased oxidative stress, mitochondrial dysfunction, and inflammation [2]. Recently, it has been reported that various hormones including growth hormone (GH) are involved in the development of NASH [3].

In patients with hypothalamic and pituitary dysfunction display a development of NAFLD [4]. Several reports have suggested that such hepatic impairment may be particularly related to growth hormone deficiency (GHD). Adult GHD (AGHD) is characterized by a decreased serum IGF-I level, increased visceral adiposity, and abnormal lipid profile [5]. Ichikawa et al. showed that hepatic steatosis was more frequently observed in hypopituitary patients with GHD than in patients without GHD [6]. In another case of AGHD accompanied by NASH and hyperlipidemia, GH replacement therapy drastically reversed NASH [7]. Moreover, it has been reported that the prevalence of NAFLD is 6.4-fold higher in patients with AGHD than in age-, sex-, and BMI-matched control subjects. In addition, GH replacement therapy improved these hepatic abnormalities in the patients [8]. These data strongly suggest that the deficiencies in GH and IGF-I are involved in the development of NAFLD/NASH [3]; however, the precise underlying mechanism remains to be elucidated.

With regard to the mechanistic action of GH, it has been shown that specific deletion of GH receptor (GHR) in hepatocytes leads to steatosis with an impaired lipid metabolism [9]. Furthermore, liver-specific deletion of JAK2 [10] or STAT5 [11], [12] in mice results in steatosis, suggesting the importance of downstream signaling of GHR in the lipid metabolism of the hepatocytes. On the other hand, in an animal model of liver cirrhosis, exogenous IGF-I expression in the liver reduced fibrosis and ultimately lead to amendment of cirrhosis, suggesting an anti-fibrotic action of IGF-I [13]. GH has a pronounced lipolytic effect, particularly in the visceral fat [14]. Because visceral adiposity is closely related with development of NAFLD, it is plausible that GH exerts its effect by reducing the visceral fat as an indirect mechanism in vivo. These findings suggest that direct, indirect, and plural actions of GH and IGF-I are closely inter-reacted and contribute to occurrence of NAFLD. However, the relative contributions of GH and IGF-I in the liver remain controversial. To elucidate the specific role of GH and IGF-I in the liver, we analyzed a GH-deficient animal model, spontaneous dwarf rat (SDR) and investigated the effect of GH and IGF-I administration on the liver.

Section snippets

Animal study

Rat experiments were performed according to the guidelines of the animal ethics committee of Kobe University Graduate School of Medicine. GH-deficient rat, spontaneous dwarf rat (SDR) was purchased from Japan SLC (Hamamatsu, Japan), and the age-matched originate strain Spragueā€“Dawley (SD) rats were used as control. To examine the phenotype in liver of SDR and SD rat, five males for each group (16-week-old) were used. Rats were housed under controlled environmental conditions (12-h light, 12-h

A GH-deficient rat model exhibited steatosis, heptocyte injury, and fibrosis in the liver and GH and IGF-I administration restored these changes

To elucidate the effect of GH-deficient status in the liver, we evaluated GH-deficient rat model. We used spontaneous dwarf rat (SDR) as a GH-deficient animal model, whose serum GH is completely absent because of the splice site mutation in the GH-1 gene [19]. Interestingly, SDR at the age of 20-week-old exhibited steatosis, hepatocyte injury, and fibrosis in the liver (Fig. 1A). The serum ALT and AST levels were elevated compared with those in the control (Fig. 1B). The triglyceride content in

Discussion

In this study we demonstrated that the GH-deficient animal model, SDR exhibited steatosis, hepatocyte injury, and fibrosis in the liver in conjunction with an elevation of liver enzyme levels, indicating that an absence of GH lead to NASH. These results were compatible with the previous reports in mice [10], [11], [12] and humans [6], [8], in which deficiency in GH or GH signaling is associated with hepatic steatosis. Furthermore, we demonstrated that administration of GH and IGF-I restored

Acknowledgments

We thank Drs. K. Takahahshi, S. Yoshioka, M. Yamamoto, K. Suda, Y. Okimura, H. Kaji, K. Iida, K. Chihara, and S. Seino for their support and fruitful discussion and C Ogata and K Imura for their excellent technical assistance. This work was supported in part by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science, and Technology 19591077 and 70301281 and in part by Grants-in-Aid for Scientific Research (research on hypothalamic-hypophyseal

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