Growth Hormone Releasing Hormone Reduces Plasma Markers of Immune Activation and Hepatic Immune Pathways in Nonalcoholic Fatty Liver Disease

Introduction: The GH/IGF-1 axis affects multiple metabolic pathways, and animal models demonstrate that it also modulates immune function. Little is known, however, regarding effects of augmenting GH secretion on immune function in humans. This study used proteomics and gene set enrichment analysis to assess effects of a GH releasing hormone (GHRH) analog, tesamorelin, on circulating immune markers and immune-related gene pathways in the liver in people with HIV (PWH) and NAFLD. We hypothesized that tesamorelin would decrease circulating markers of immune activation in conjunction with previously reported reductions in visceral fat and hepatic triglyceride. Methods: 92 biomarkers associated with immune function (Olink Immuno-Oncology panel) were measured in plasma samples from 61 PWH with NAFLD who participated in a double-blind, randomized, 12-month trial of tesamorelin versus identical placebo. Proteins differentially altered by tesamorelin at a false discovery rate < 0.1 were considered significantly changed. Gene set enrichment analysis targeted to immune pathways was subsequently performed on liver tissue from serial biopsies. Results: Compared to placebo, tesamorelin decreased circulating concentrations of 13 proteins, including four chemokines (C-C Motif Chemokine Ligands 3 [CCL3, effect size -0.38 Log(2) fold change], 4 [CCL4, -0.36 Log(2) fold change], and 13 [CCL13 or MCP4, -0.42 Log(2) fold change] and interleukin-8 [-0.50 Log(2) fold change]), two cytokines (interleukin-10 [-0.32 Log(2) fold change] and cytokine stimulating factor 1 [-0.22 Log(2) fold change]), and four T-cell associated molecules (CD8A [-0.37 Log(2) fold change], Cytotoxic And Regulatory T Cell Molecule [CRTAM, -0.47 Log(2) fold change], granzyme A [-0.53 Log(2) fold change], and adhesion G protein-coupled receptor G1 [ADGRG1, -0.54 Log(2) fold change]), as well as arginase-1 [-0.95 Log(2) fold change], galectin-9 [-0.26 Log(2) fold change], and hepatocyte growth factor [-0.30 Log(2) fold change]. No proteins in the panel were significantly increased by tesamorelin. Network analysis indicated close interaction among the gene pathways responsible for the reduced proteins, with imputational analyses suggesting down regulation of a closely related cluster of immune pathways. Targeted transcriptomics using tissue from liver biopsy confirmed an end-organ signal of down-regulated immune pathways, including pathways involved in antigen presentation, complement activation, toll like receptor and inflammatory signaling, and T-cell activation. Conclusions: Long-term treatment with tesamorelin decreased circulating markers of T-cell and monocyte/macrophage activity, with corresponding downregulation of immune pathways in the liver. These findings suggest that augmenting pulsatile GH may ameliorate immune activation in a population with metabolic dysregulation and systemic inflammation.