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

Barbara Renga; Daniela Francisci; Adriana Carino; Silvia Marchianò; Sabrina Cipriani; Maria Chiara Monti; Rachele Del Sordo; Elisabetta Schiaroli; Eleonora Distrutti; Franco Baldelli; Stefano Fiorucci

doi:10.1038/srep15403

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

Sci Rep. 2015 Oct 15:5:15403. doi: 10.1038/srep15403.

Affiliations

¹ Department of Surgical and Biomedical Sciences, Section of gastroenterology, University of Perugia, Perugia, Italy.
² Department of Medicine, Section of Infectious diseases, University of Perugia, Perugia, Italy.
³ Department of Biomedical and Pharmaceutical Sciences, University of Salerno, Fisciano, Italy.
⁴ Department of Experimental Medicine and Biochemical Sciences, Section of Anatomic Pathology and Histology, University of Perugia, Perugia, Italy.
⁵ Hospital S.M. Misericordia, Perugia, Italy.

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.

MeSH terms

AIDS Vaccines / immunology
Animals
Cells, Cultured
Cholesterol / analogs & derivatives
Cholesterol / analysis
HIV / metabolism*
Hep G2 Cells
Hepatocytes / cytology
Hepatocytes / metabolism
Humans
Lipid Metabolism* / drug effects
Liver / metabolism*
Liver X Receptors
Mediator Complex Subunit 1 / genetics
Mediator Complex Subunit 1 / metabolism
Mice
Mice, Inbred C57BL
Orphan Nuclear Receptors / antagonists & inhibitors
Orphan Nuclear Receptors / genetics
Orphan Nuclear Receptors / metabolism
Peptide Fragments / genetics
Peptide Fragments / metabolism*
Peptide Fragments / pharmacology
Receptors, Cytoplasmic and Nuclear / genetics
Receptors, Cytoplasmic and Nuclear / metabolism
Recombinant Proteins / biosynthesis
Recombinant Proteins / immunology
Recombinant Proteins / pharmacology
STAT Transcription Factors / chemistry
STAT Transcription Factors / metabolism
Signal Transduction / drug effects
Sterol Regulatory Element Binding Protein 1 / genetics
Sterol Regulatory Element Binding Protein 1 / metabolism
Trans-Activators / genetics
Trans-Activators / metabolism
Transcriptional Activation / drug effects
env Gene Products, Human Immunodeficiency Virus / genetics
env Gene Products, Human Immunodeficiency Virus / metabolism*
env Gene Products, Human Immunodeficiency Virus / pharmacology

Substances

AIDS Vaccines
Liver X Receptors
MED1 protein, human
Mediator Complex Subunit 1
NR1H3 protein, human
Nr1h3 protein, mouse
Orphan Nuclear Receptors
Peptide Fragments
Receptors, Cytoplasmic and Nuclear
Recombinant Proteins
STAT Transcription Factors
Sterol Regulatory Element Binding Protein 1
Trans-Activators
env Gene Products, Human Immunodeficiency Virus
p17 gag peptide, human immunodeficiency virus
Cholesterol