Targeted proteomic and transcriptomic analysis of 9 plasma proteins in HIV-associated NAFLD patients from a tesamorelin randomized trial, delineating the downstream protein-level effects of tesamorelin on hepatic inflammation, tissue repair, and cell division pathways—bridging transcriptomic gene set changes to circulating protein biomarkers. Provides protein-level mechanistic validation of tesamorelin's hepatic effects. Establishes specific circulating protein signatures of tesamorelin's anti-fibrotic mechanism in HIV-NAFLD—translating prior transcriptomic findings to measurable blood-based pharmacodynamic markers that could guide monitoring of tesamorelin therapy in clinical practice.
Abstract
NAFLD is a leading comorbidity in HIV with an exaggerated course compared to the general population. Tesamorelin has been demonstrated to reduce liver fat and prevent fibrosis progression in HIV-associated NAFLD. We further showed that tesamorelin downregulated hepatic gene sets involved in inflammation, tissue repair, and cell division. Nonetheless, effects of tesamorelin on individual plasma proteins pertaining to these pathways are not known. Leveraging our prior randomized-controlled trial and transcriptomic approach, we performed a focused assessment of 9 plasma proteins corresponding to top leading edge genes within differentially modulated gene sets. Tesamorelin led to significant reductions in vascular endothelial growth factor A (VEGFA, log-fold change - 0.20 ± 0.35 vs. 0.05 ± 0.34, P = 0.02), transforming growth factor beta 1 (TGFB1, - 0.35 ± 0.56 vs. - 0.05 ± 0.43, P = 0.05), and macrophage colony stimulating factor 1 (CSF1, - 0.17 ± 0.21 vs. 0.02 ± 0.20, P = 0.004) versus placebo. Among tesamorelin-treated participants, reductions in plasma VEGFA (r = 0.62, P = 0.006) and CSF1 (r = 0.50, P = 0.04) correlated with a decline in NAFLD activity score. Decreases in TGFB1 (r = 0.61, P = 0.009) and CSF1 (r = 0.64, P = 0.006) were associated with reduced gene-level fibrosis score. Tesamorelin suppressed key angiogenic, fibrogenic, and pro-inflammatory mediators. CSF1, a regulator of monocyte recruitment and activation, may serve as an innovative therapeutic target for NAFLD in HIV. Clinical Trials Registry Number: NCT02196831.
Authors
Fourman, Lindsay T; Stanley, Takara L; Billingsley, James M; Sui, Shannan J Ho; Feldpausch, Meghan N; Boutin, Autumn; Zheng, Isabel; McClure, Colin M; Corey, Kathleen E; Torriani, Martin; Kleiner, David E; Hadigan, Colleen M; Chung, Raymond T; Grinspoon, Steven K