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

Year: 2021
Type: article
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
DOI: 10.1038/s41598-021-89966-y
Authors: 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
Institutions: Harvard University, Massachusetts General Hospital, National Cancer Institute, Center for Cancer Research, National Institutes of Health, National Institute of Allergy and Infectious Diseases
Language: English
Subfield: Hepatology
Field: Medicine
Open Access status: gold
Estimated APC paid: $1,990
Funders: Massachusetts General Hospital, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Tesamorelin Effects on Liver Fat and Histology in HIV: A Collaborative U01 Grant, Institutional Career Development Core, In Utero HIV Exposure and Metabolic Disease Risk in HIV-Uninfected Young Adults, HIV-Associated Macrophage Alterations and Progressive Liver Disease, HIV, HCV, Hippo, and Liver Disease Progression, Durable Alteration of the Human Immune system after Infection or Immunotherapy, Harvard University Center for AIDS Research, Boston Area Nutrition Obesity Research Center (NORC)
OpenAlex ID: W3160832982
FWCI: 0.587
Cites: 26
Cited by: 10
Related to: 10