The Role of Growth Hormone and Insulin Growth Factor 1 in the Development of Non-Alcoholic Steato-Hepatitis: A Systematic Review

Figure 1. Different characteristics contributing to the transition from a healthy liver to the development of NASH.

Figure 2. PRISMA flow diagram of the study.

Figure 3. Pathogenic mechanisms in the development of NASH. Environmental, genetic, and metabolic factors are thought to be involved in the pathogenesis of NASH. Changes in the intestinal microbiome result in increased serum FFA and proinflammatory cyto/chemokine levels, believed to be the leading causes of progression to NASH. Activation of liver KCs results in the release of CCL2 TNFα, IL-1, IL-6, and other proinflammatory cytokines, leading to the recruitment of immune system cells, hepatic stellate cell activation, and macrophage-mediated inflammation.

Figure 4. Effects of growth hormone deficiency on liver. Both hepatocyte lipotoxicity and immune-mediated inflammation are considered pivotal events in the pathogenesis of NASH. Growth hormone deficiency causes up-regulation of genes involved in de novo lipogenesis, such as CD36. Increased hepatic CD36 expression leads to higher lipogenesis, increased triglycerides (Tg) accumulation, and insulin resistance, favoring hepatic steatosis. Excess dietary fats and simple carbohydrate intake activate transcription factors that control de novo lipogenesis and mitochondrial function. Dysregulation of βoxidation induces endoplasmic reticulum (ER) stress, oxidative stress, and inflammasome activation. These events collectively lead to hepatic inflammation and fibrosis. A decrease in insulin-like growth factor-1 (IGF-1) results in insulin resistance and mitochondrial dysfunction that may further contribute to the development of NASH. Moreover, decreased IGF-1 may promote hepatic fibrosis, as IGF-1 directly inactivates hepatic stellate cells.

Figure 5. GH leads to dimerization of its receptor (GHR), promoting phosphorylation of Janus kinase (JAK) and consequent activation of STAT proteins. This event results in the dimerization and translocation of STATs to the nucleus. In the nucleus, STAT proteins are capable of binding to the IGF-1 promoter, initiating the transcription of this gene. In circulation, much of IGF-1 is bound by IGF-binding proteins (IGFBPs). Among these, IGFBP-3 is the primary carrier of IGF-1 in plasma, and it acts as a carrier protein and regulator of IGF-1 bioavailability.