Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach

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...

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Autores principales:	Lindsay T. Fourman, Takara L. Stanley, James M. Billingsley, Shannan J. Ho Sui, Meghan N. Feldpausch, Autumn Boutin, Isabel Zheng, Colin M. McClure, Kathleen E. Corey, Martin Torriani, David E. Kleiner, Colleen M. Hadigan, Raymond T. Chung, Steven K. Grinspoon
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/968ba8285b7d4c9dac1b0917f40794e7
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spelling	oai:doaj.org-article:968ba8285b7d4c9dac1b0917f40794e72021-12-02T15:53:10ZDelineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach10.1038/s41598-021-89966-y2045-2322https://doaj.org/article/968ba8285b7d4c9dac1b0917f40794e72021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89966-yhttps://doaj.org/toc/2045-2322Abstract 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: NCT02196831Lindsay T. FourmanTakara L. StanleyJames M. BillingsleyShannan J. Ho SuiMeghan N. FeldpauschAutumn BoutinIsabel ZhengColin M. McClureKathleen E. CoreyMartin TorrianiDavid E. KleinerColleen M. HadiganRaymond T. ChungSteven K. GrinspoonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lindsay T. Fourman Takara L. Stanley James M. Billingsley Shannan J. Ho Sui Meghan N. Feldpausch Autumn Boutin Isabel Zheng Colin M. McClure Kathleen E. Corey Martin Torriani David E. Kleiner Colleen M. Hadigan Raymond T. Chung Steven K. Grinspoon Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach
description	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
format	article
author	Lindsay T. Fourman Takara L. Stanley James M. Billingsley Shannan J. Ho Sui Meghan N. Feldpausch Autumn Boutin Isabel Zheng Colin M. McClure Kathleen E. Corey Martin Torriani David E. Kleiner Colleen M. Hadigan Raymond T. Chung Steven K. Grinspoon
author_facet	Lindsay T. Fourman Takara L. Stanley James M. Billingsley Shannan J. Ho Sui Meghan N. Feldpausch Autumn Boutin Isabel Zheng Colin M. McClure Kathleen E. Corey Martin Torriani David E. Kleiner Colleen M. Hadigan Raymond T. Chung Steven K. Grinspoon
author_sort	Lindsay T. Fourman
title	Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach
title_short	Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach
title_full	Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach
title_fullStr	Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach
title_full_unstemmed	Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach
title_sort	delineating tesamorelin response pathways in hiv-associated nafld using a targeted proteomic and transcriptomic approach
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/968ba8285b7d4c9dac1b0917f40794e7
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Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach

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