Growth hormone and nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a prevalent cause of liver disease and metabolic comorbidities. Obesity is strongly associated with NAFLD and is also a state of relative deficiency of growth hormone (GH). Evidence supports a role of reduced GH and insulin-like growth factor-1 (IGF-1) in NAFLD pathogenesis. Physiological actions of GH in the liver include suppression of de novo lipogenesis (DNL) and promotion of lipid beta-oxidation, and GH also appears to have anti-inflammatory actions. Physiologic actions of IGF-1 include suppression of inflammatory and fibrogenic pathways important in the evolution from steatosis to steatohepatitis and fibrosis. Rodent models of impaired hepatic GH signaling show the development of steatosis, sometimes accompanied by inflammation, hepatocellular damage, and fibrosis, and these changes are ameliorated by treatment with GH and/or IGF-1. In humans, individuals with GH deficiency and GH resistance demonstrate an increased prevalence of NAFLD compared to controls, with improvement in hepatic lipid, steatohepatitis, and fibrosis following GH replacement. As a corollary, individuals with GH excess demonstrate lower hepatic lipid compared to controls along with increased hepatic lipid following treatment to normalize GH levels. Clinical trials demonstrate that augmentation of GH reduces hepatic lipid content in individuals with NAFLD and may also ameliorate steatohepatitis and fibrosis. Taken together, evidence supports an important role for perturbations in the GH/IGF-1 axis as one of the pathogenic mechanisms of NAFLD and suggests that further study is needed to assess whether augmentation of GH and/or IGF-1 may be a safe and effective therapeutic strategy for NAFLD.

Keywords: growth hormone; insulin-like growth factor-1; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; releasing hormone.

Figure 1.

Regulation of GH secretion. GH is synthesized and secreted by the anterior pituitary. Pulsatile secretion is regulated primarily by two hypothalamic hormones: somatostatin, which inhibits GH secretion, and GHRH, which stimulates GH secretion. GH negatively regulates its own secretion through hypothalamic signaling, and IGF-1, synthesized in response to GH signaling, also exerts negative feedback at the level of the pituitary and the hypothalamus. Ghrelin stimulates GH secretion at the anterior pituitary and hypothalamus. GH: growth hormone, GHRH: growth hormone releasing hormone, IGF-1: insulin-like growth factor-1.

Figure 2.

Effects of GH and IGF-1 on NAFLD and NASH. Lipid flux to the liver includes FFA from adipose tissue lipolysis, dietary sources, and DNL. Sources of “outflow” from the hepatic FFA pool include synthesis of triglyceride and export as VLDL as well as lipid beta-oxidation. GH suppresses DNL and increases lipid beta-oxidation. GH also increases epidermal growth factor receptor, leading to liver regeneration, and exerts anti-inflammatory effects in the liver. IGF-1 also signals in immune cells in the liver to exert anti-inflammatory and anti-fibrotic effects and to induce HSC senescence. DNL: de novo lipogenesis, EGFR: epidermal growth factor receptor, FFA: free fatty acid, GH: growth hormone, GHR: growth hormone receptor, HSC: hepatic stellate cell, IGF-1: insulin-like growth factor-1, JAK2: Janus kinase 2, STAT5b: signal transducer and activator of transcription 5, VLDL: very-low-density lipoprotein.