The HIV matrix protein p17 induces hepatic lipid accumulation via modulation of nuclear receptor transcriptoma

Abstract

Liver disease is the second most common cause of mortality in HIV-infected persons. Exactly how HIV infection per se affects liver disease progression is unknown. Here we have investigated mRNA expression of 49 nuclear hormone receptors (NRs) and 35 transcriptional coregulators in HepG2 cells upon stimulation with the HIV matrix protein p17. This viral protein regulated mRNA expression of some NRs among which LXRα and its transcriptional co-activator MED1 were highly induced at mRNA level. Dissection of p17 downstream intracellular pathway demonstrated that p17 mediated activation of Jak/STAT signaling is responsible for the promoter dependent activation of LXR. The treatment of both HepG2 as well as primary hepatocytes with HIV p17 results in the transcriptional activation of LXR target genes (SREBP1c and FAS) and lipid accumulation. These effects are lost in HepG2 cells pre-incubated with a serum from HIV positive person who underwent a vaccination with a p17 peptide as well as in HepG2 cells pre-incubated with the natural LXR antagonist gymnestrogenin. These results suggest that HIV p17 affects NRs and their related signal transduction thus contributing to the progression of liver disease in HIV infected patients.

Interferon‐γ decreases ATP‐binding cassette subfamily G member 1‐mediated cholesterol efflux through small ubiquitin‐like modifier/ubiquitin‐dependent liver X receptor‐α degradation in macrophages

“…IFN-γ induces its cellular response through Jak-STAT1 signaling [8]. Besides IFN-γ , this inflammatory signal can be activated by lipopolysaccharide, gangliosides, thrombin, and HIV matrix protein p17 [16,17]. However, only Renga et al [17] reported that the HIV matrix protein p17 mediated induction of LXR-α occurred via promoter-dependent recruitment of STAT-1 transcription factors in HepG2 cell, whose neither cell model nor research background were similar with ours.…”

Antiretroviral Therapy-Induced Dysregulation of Gene Expression and Lipid Metabolism in HIV+ Patients: Beneficial Role of Antioxidant Phytochemicals

“…Liver lipid accumulation induced by HIV infection deserves special attention, besides the glucose and lipid metabolism derangements which mean the risk of cardiovascular disease. Liver illness is the second most common cause of death in HIV-infected people; therefore, the role of HIV matrix protein p17, a multifactorial protein that mediates viral replication and the infection of immune T-cells and monocytes, besides the hepatic stellate cells, was described [ 111 ]. Protein p17 enhanced the expression and transcriptional activity of LXR and its coactivator, the mediator complex subunit-1 (MED1), via the activation of Jak/STAT signaling, which resulted in hepatic lipid accumulation via activation of the LXR/SREBP1c (sterol regulatory element-binding transcription factor 1) lipogenic pathway.…”

“…ROS production is mediated by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) family complex as NOX1, NOX2, NOX4, and NOX5 [ 5 , 124 ]. NOX members are found in muscle tissue and represent the primary sources of ROS; its activity has been investigated in conditions such as hypertension, hypercholesterolemia, and endothelial dysfunction [ 110 , 111 , 112 , 125 , 126 , 127 ]. Another enzyme that generates ROS is xanthine oxidoreductase, principally found in the liver and gut, although distributed in smaller proportions in the lungs, kidneys, heart, and brain plasma.…”

Infezione da HIV e rischio cardiovascolare: il ruolo di PCSK9.

“…Ciò sembra suggerire l'ipotesi che la viremia e l'immunosoppressione possano contribuire ad aumentare i livelli plasmatici di PCSK9 nell'infezione da HIV non trattata. A tale proposito, è stato riportato che la proteina della matrice virale p17 è in grado di indurre l'espressione epatocitaria delle SREBPs (29), che a loro volta possono indurre la trascrizione di PCSK9 (1). Tuttavia, non è da escludere uno scenario alternativo in cui PCSK9 stesso sia in grado di promuovere l'infezione da HIV.…”