The Role of Growth Hormone and Insulin-Like Growth Factor-I in the Liver

Abstract

Adult growth hormone deficiency (GHD) is characterized by metabolic abnormalities associated with visceral obesity, impaired quality of life, and increased mortality. Patients with adult GHD show increased prevalence of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), and growth hormone (GH) replacement therapy has been shown to improve these conditions. It has also been demonstrated that a decrease in the GH insulin-like growth factor-I (IGF-I) axis is closely associated with the progression of general NAFLD, suggesting a physiological role of these hormones for the maintenance of the liver. NASH histologically demonstrates inflammation, necrosis, and fibrosis, in addition to steatosis (and is a serious disease because it can progress to liver cirrhosis and hepatocellular carcinoma in a subset of cases). While fibrosis determines the prognosis of the patient, efficacious treatment for fibrosis is crucial; however, it has not yet been established. Recent studies have clarified the essential roles of GH and IGF-I in the liver. GH profoundly reduces visceral fat, which plays an important role in the development of NAFLD. Furthermore, GH directly reduces lipogenesis in the hepatocytes. IGF-I induces cellular senescence and inactivates hepatic stellate cells, therefore ameliorating fibrosis. IGF-I treatment has been shown to improve animal models of NASH and cirrhosis, suggesting potential clinical applications of IGF-I in these conditions. In this review, I will focus on the important roles of GH and IGF-I in the liver, their underlying mechanisms, and their potential therapeutic applications.

Keywords: adult growth hormone deficiency; cirrhosis; growth hormone; hepatic stellate cells; insulin-like growth factor-I; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis.

Figure 1

The growth hormone (GH) receptor signaling and target genes in the liver. GH binds to the GH receptor and activates the janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) signaling pathway. Several target genes of STAT5, including insulin-like growth factor-I (IGF-I) and peroxisome proliferator-activated receptor γ (PPARγ), play an essential role in the liver. The decrease in GH receptor signaling induces a decrease in IGF-I expression, resulting in the progression of fibrosis. At the same time, an increase in the expression of PPARγ, peroxisome proliferative activated receptor γ, coactivator-1α(PGC1α), cluster of differentiation 36 (CD36), and lipoprotein lipase (LPL), and a decrease in the expression of very low density lipoprotein receptor (VLDLR), cause the impaired lipid metabolism, leading to steatosis. GH, growth hormone; IGF-I, insulin-like growth factor-I.

Figure 2

The role of GH and IGF-I in the liver. GH and IGF-I exert their effects in multiple mechanisms. GH reduces visceral fat that plays a pivotal role in the development of non-alcoholic steatohepatitis (NASH). GH directly decreases lipogenesis in the hepatocytes. IGF-I improves insulin resistance, decreases reactive oxygen species (ROS), improves mitochondrial function, and decreases triglyceride accumulation in the hepatocytes. In addition, IGF-I induces senescence and inactivates HSCs and limits fibrosis.