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, log2-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
Highlights
In the setting of the modern obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become a growing threat to public health
Of 61 participants with HIV-associated NAFLD in the randomized-controlled trial, 58 individuals had a plasma protein panel obtained at baseline that was available for analysis
In the current study, elaborating upon a prior hepatic transcriptomic analysis, we examined effects of tesamorelin on key plasma proteins in people living with HIV (PLWH) with NAFLD
Summary
In the setting of the modern obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become a growing threat to public health. Using gene set enrichment analysis (GSEA) of hallmark gene sets, we found that tesamorelin led to hepatic upregulation of gene sets involved in oxidative phosphorylation, and downregulation of gene sets pertaining to inflammation, tissue repair, and cell d ivision[8] Leveraging these results, we have performed a focused proteomic analysis of top leading edge genes in key pathways flagged by our transcriptomic analysis. We compared changes in protein levels by treatment status, and assessed associations of such changes with radiographic, histologic, and transcriptomic indices of NAFLD phenotype Using this overlaid transcriptomic and proteomic approach, we identified novel effects of tesamorelin to reduce 3 plasma proteins in proportion to a decline in NAFLD severity. The current study deepens our understanding of the biologic effects of GH axis augmentation among PLWH with NAFLD and introduces innovative potential therapeutic targets and protein signatures of treatment response that warrant further investigation
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