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Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic
Lindsay T Fourman1, Takara L Stanley1, James M Billingsley2
1Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street 5LON207, Boston, MA, 02114, USA.
Scientific Reports
|May 19, 2021
Summary
Tesamorelin significantly reduced key plasma proteins, including VEGFA, TGFB1, and CSF1, in patients with HIV-associated NAFLD. These reductions correlated with improved NAFLD activity and fibrosis scores, suggesting therapeutic potential.
Area of Science:
- Hepatology and Infectious Diseases
- Endocrinology and Metabolism
- Immunology
Background:
- Non-alcoholic fatty liver disease (NAFLD) is a significant comorbidity in individuals with HIV, often presenting with a more severe course than in the general population.
- Tesamorelin has previously shown efficacy in reducing liver fat and preventing fibrosis progression in HIV-associated NAFLD.
- Previous transcriptomic analysis indicated tesamorelin downregulates hepatic gene sets involved in inflammation, tissue repair, and cell division.
Purpose of the Study:
- To investigate the effects of tesamorelin on individual plasma protein levels related to inflammation, tissue repair, and cell division pathways in HIV-associated NAFLD.
- To assess the correlation between changes in specific plasma protein levels and clinical outcomes, including NAFLD activity and fibrosis scores.
Main Methods:
- A focused assessment of 9 plasma proteins was conducted, leveraging data from a prior randomized-controlled trial and transcriptomic analysis.
- Plasma levels of vascular endothelial growth factor A (VEGFA), transforming growth factor beta 1 (TGFB1), and macrophage colony stimulating factor 1 (CSF1) were measured and compared between tesamorelin and placebo groups.
- Correlations between plasma protein changes and NAFLD activity score, as well as gene-level fibrosis score, were analyzed.
Main Results:
- Tesamorelin treatment resulted in significant reductions in plasma VEGFA, TGFB1, and CSF1 compared to placebo.
- Reductions in plasma VEGFA and CSF1 among tesamorelin-treated participants correlated with a decline in NAFLD activity score.
- Decreases in TGFB1 and CSF1 were associated with reduced gene-level fibrosis scores, indicating suppression of angiogenic, fibrogenic, and pro-inflammatory mediators.
Conclusions:
- Tesamorelin effectively suppresses key angiogenic, fibrogenic, and pro-inflammatory plasma protein mediators in HIV-associated NAFLD.
- Macrophage colony stimulating factor 1 (CSF1) may represent an innovative therapeutic target for NAFLD in the context of HIV infection.
- The findings support tesamorelin's role in managing liver disease complications in HIV patients and highlight CSF1 as a potential biomarker and therapeutic target.
