title: 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.
authors.affiliation: Department of Surgical and Biomedical Sciences, Section of gastroenterology, University of Perugia, Perugia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.affiliation: Department of Medicine, Section of Infectious diseases, University of Perugia, Perugia, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Francisci
authors.affiliation: Department of Surgical and Biomedical Sciences, Section of gastroenterology, University of Perugia, Perugia, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Carino
authors.affiliation: Department of Surgical and Biomedical Sciences, Section of gastroenterology, University of Perugia, Perugia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marchianò
authors.affiliation: Department of Medicine, Section of Infectious diseases, University of Perugia, Perugia, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cipriani
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Salerno, Fisciano, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Chiara Monti
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, Section of Anatomic Pathology and Histology, University of Perugia, Perugia, Italy.
authors.forename: Rachele
authors.initials: R
authors.lastname: Del Sordo
authors.affiliation: Department of Medicine, Section of Infectious diseases, University of Perugia, Perugia, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Schiaroli
authors.affiliation: Hospital S.M. Misericordia, Perugia, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Distrutti
authors.affiliation: Department of Medicine, Section of Infectious diseases, University of Perugia, Perugia, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Baldelli
authors.affiliation: Department of Surgical and Biomedical Sciences, Section of gastroenterology, University of Perugia, Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000031:analogs & derivatives / Q000032:analysis; D006678:HIV / Q000378:metabolism*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D056913:Mediator Complex Subunit 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology; D050791:STAT Transcription Factors / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D016915:AIDS Vaccines; D000071518:Liver X Receptors; C538855:MED1 protein, human; D056913:Mediator Complex Subunit 1; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D010446:Peptide Fragments; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D050791:STAT Transcription Factors; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators; D054299:env Gene Products, Human Immunodeficiency Virus; C473991:p17 gag peptide, human immunodeficiency virus; D002784:Cholesterol