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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 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.

SUBMITTER: Fourman LT

PROVIDER: S-EPMC8131688 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD.

Project description:Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity among people living with HIV that has a more aggressive course than NAFLD among the general population. In a recent randomized placebo-controlled trial, we demonstrated that the growth hormone-releasing hormone analog tesamorelin reduced liver fat and prevented fibrosis progression in HIV-associated NAFLD over 1 year. As such, tesamorelin is the first strategy that has shown to be effective against NAFLD among the population with HIV. The current study leveraged paired liver biopsy specimens from this trial to identify hepatic gene pathways that are differentially modulated by tesamorelin versus placebo. Using gene set enrichment analysis, we found that tesamorelin increased hepatic expression of hallmark gene sets involved in oxidative phosphorylation and decreased hepatic expression of gene sets contributing to inflammation, tissue repair, and cell division. Tesamorelin also reciprocally up- and downregulated curated gene sets associated with favorable and poor hepatocellular carcinoma prognosis, respectively. Notably, among tesamorelin-treated participants, these changes in hepatic expression correlated with improved fibrosis-related gene score. Our findings inform our knowledge of the biology of pulsatile growth hormone action and provide a mechanistic basis for the observed clinical effects of tesamorelin on the liver.

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Effects of Tesamorelin on Hepatic Transcriptomic Signatures in HIV-Associated NAFLD

Project description:Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity among people living with HIV with a more aggressive course than in the general population. In a recent randomized placebo-controlled trial, we demonstrated that the growth hormone-releasing hormone analogue tesamorelin reduced liver fat and prevented fibrosis progression in HIV-associated NAFLD over one year. In the current study, we leveraged paired liver biopsy specimens from this trial to identify hepatic gene pathways that are differentially modulated by tesamorelin versus placebo to gain key insights into the biological underpinnings of its clinical effects.

2020-09-08 | GSE150026 | GEO

Effects of Tesamorelin on Hepatic Transcriptomic Signatures in HIV-Associated NAFLD

Project description:Effects of Tesamorelin on Hepatic Transcriptomic Signatures in HIV-Associated NAFLD

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Global response of Plasmodium falciparum to hyperoxia: a combined transcriptomic and proteomic approach.

Project description:BACKGROUND: Over its life cycle, the Plasmodium falciparum parasite is exposed to different environmental conditions, particularly to variations in O2 pressure. For example, the parasite circulates in human venous blood at 5% O2 pressure and in arterial blood, particularly in the lungs, at 13% O2 pressure. Moreover, the parasite is exposed to 21% O2 levels in the salivary glands of mosquitoes. METHODS: To study the metabolic adaptation of P. falciparum to different oxygen pressures during the intraerythrocytic cycle, a combined approach using transcriptomic and proteomic techniques was undertaken. RESULTS: Even though hyperoxia lengthens the parasitic cycle, significant transcriptional changes were detected in hyperoxic conditions in the late-ring stage. Using PS 6.0 ™ software (Ariadne Genomics) for microarray analysis, this study demonstrate up-expression of genes involved in antioxidant systems and down-expression of genes involved in the digestive vacuole metabolism and the glycolysis in favour of mitochondrial respiration. Proteomic analysis revealed increased levels of heat shock proteins, and decreased levels of glycolytic enzymes. Some of this regulation reflected post-transcriptional modifications during the hyperoxia response. CONCLUSIONS: These results seem to indicate that hyperoxia activates antioxidant defence systems in parasites to preserve the integrity of its cellular structures. Moreover, environmental constraints seem to induce an energetic metabolism adaptation of P. falciparum. This study provides a better understanding of the adaptive capabilities of P. falciparum to environmental changes and may lead to the development of novel therapeutic targets.

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Complement-Opsonized HIV Modulates Pathways Involved in Infection of Cervical Mucosal Tissues: A Transcriptomic and Proteomic Study.

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Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways.

Project description:In Drosophila, endoplasmic reticulum (ER) stress activates the protein kinase R-like endoplasmic reticulum kinase (dPerk). dPerk can also be activated by defective mitochondria in fly models of Parkinson's disease caused by mutations in pink1 or parkin. The Perk branch of the unfolded protein response (UPR) has emerged as a major toxic process in neurodegenerative disorders causing a chronic reduction in vital proteins and neuronal death. In this study, we combined microarray analysis and quantitative proteomics analysis in adult flies overexpressing dPerk to investigate the relationship between the transcriptional and translational response to dPerk activation. We identified tribbles and Heat shock protein 22 as two novel Drosophila activating transcription factor 4 (dAtf4) regulated transcripts. Using a combined bioinformatics tool kit, we demonstrated that the activation of dPerk leads to translational repression of mitochondrial proteins associated with glutathione and nucleotide metabolism, calcium signalling and iron-sulphur cluster biosynthesis. Further efforts to enhance these translationally repressed dPerk targets might offer protection against Perk toxicity.

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Transcriptomic profiling of a multiethnic pediatric NAFLD cohort reveals genes and pathways associated with disease.

Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in children. The mechanisms that drive NAFLD disease progression in this specific patient population remain poorly defined. In this study, we obtained liver biopsy samples from a multiethnic cohort of pediatric patients with NAFLD (n = 52, mean age = 13.6 years) and healthy liver controls (n = 5). We analyzed transcriptomic changes associated with NAFLD stages using high-throughput RNA sequencing. Unsupervised clustering as well as pairwise transcriptome comparison distinguished NAFLD from healthy livers. We identified perturbations in pathways including calcium and insulin/glucose signaling occurring early in NAFLD disease, before the presence of histopathologic evidence of advanced disease. Transcriptomic comparisons identified a 25-gene signature associated with the degree of liver fibrosis. We also identified expression of the insulin-like growth factor binding protein (IGFBP) gene family (1/2/3/7) as correlating with disease stages, and it has the potential to be used as a peripheral biomarker in NAFLD. Comparing our data set with publicly available adult and adolescent transcriptomic data, we identified similarities and differences in pathway enrichment and gene-expression profiles between adult and pediatric patients with NAFLD. Regulation of genes including interleukin-32, IGFBP1, IGFBP2, and IGFBP7 was consistently found in both NAFLD populations, whereas IGFBP3 was specific to pediatric NAFLD. Conclusion: This paper expands our knowledge on the molecular mechanisms underlying pediatric NAFLD. It identifies potential biomarkers and directs us toward new therapies in this population.

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Visceral fat reduction with tesamorelin is associated with improved liver enzymes in HIV.

Project description:OBJECTIVE:Tesamorelin reduces visceral adipose tissue (VAT) in HIV. We investigated whether reductions in VAT with tesamorelin are associated with changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). DESIGN AND METHODS:We utilized data from two multicenter Phase III trials of tesamorelin among 806 HIV-infected patients with abdominal obesity. These studies showed that the majority of patients treated with tesamorelin are 'responders', defined a priori by the Food and Drug Administration as achieving at least 8% reduction in VAT. In the current analysis, we sought to examine the impact of VAT reduction on ALT and AST among patients participating in the Phase III trials with baseline elevated ALT or AST. Within this group, we compared changes in ALT and AST in VAT responders vs. nonresponders after 26 weeks of treatment, and then assessed the effects of drug discontinuation on these endpoints over a subsequent 26-week period. RESULTS:At baseline, VAT was positively associated with ALT (P?=?0.01). In study participants assigned to tesamorelin with baseline ALT or AST more than 30?U/l, VAT responders experienced greater reductions in ALT (-8.9?±?22.6 vs. 1.4?±?34.7?U/l, P?=?0.004) and AST (-3.8?±?12.9 vs. 0.4?±?22.4?U/l, P?=?0.04) compared with nonresponders over 26 weeks. This improvement among VAT responders persisted over 52 weeks even in those switched to placebo despite a partial reaccumulation of VAT. CONCLUSION:A clinically significant VAT reduction with tesamorelin was associated with improved liver enzymes among HIV-infected patients with abdominal obesity and elevated baseline transaminases.

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