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

Hepatic damage caused by long-term high cholesterol intake induces a dysfunctional restorative macrophage population in experimental NASH

“…Several pro-inflammatory and pro-fibrotic genes were exclusively induced in macrophages by medium and high cholesterol intake: Osmr , the receptor for Oncostatin M, is involved in macrophage recruitment and infiltration ( 41 ); Il33 , a pro-inflammatory and pro-fibrotic cytokine that can activate hepatic stellate cells and macrophages ( 42 , 43 ); Tnf , known to contribute to liver inflammation and strongly correlated to NASH severity ( 44 ); Cnr2 , which participates in obesity-induced hepatic inflammation, macrophage infiltration, and TNF and CCL2 expression ( 45 ); and Csf1 , highly expressed in NASH ( 46 ). Cholesterol reduction significantly inhibited the genes Cxcl2 and Ccl17 , known for neutrophil, macrophage, and Treg cell recruitment ( 47 , 48 ).…”

Adipose Tissue Dysfunction and Energy Balance Paradigms in People Living With HIV

“…The natural progression of HIV-associated NAFLD was assessed in a subanalysis of a double-blind trial that evaluated the effects of tesamorelin vs placebo on NAFLD ( 96 ). In the placebo group, fibrosis progressed in 38% (n = 9) of participants with HIV-associated NAFLD over a 12-month period ( 97 ).…”

“…An open-label clinical trial recently showed vitamin E decreases markers of liver fat content and hepatocyte apoptosis in PLWH with biopsy-proven NASH ( 116 ). The GHRH analog tesamorelin improves liver enzymes, hepatic steatosis, and angiogenic, fibrogenic, and pro-inflammatory mediators compared with placebo ( 96 , 117 , 118 ). The effectiveness of glucagon-like peptide-1 receptor agonists for management of NAFLD in PLWH is under study ( 119 ).…”