25-Hydroxycholesterol and inflammation in Lovastatin-deregulated mevalonate pathway. 2017

Paola Maura Tricarico, and Rossella Gratton, and Luca Braga, and Fulvio Celsi, and Sergio Crovella
Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Via dell'Istria, 65/1, 34137 Trieste, Italy. Electronic address: tricaricopa@gmail.com.

Mevalonate pathway deregulation has been observed in several diseases, including Mevalonate kinase deficiency (MKD). MKD is a hereditary auto-inflammatory disorder, due to mutations at mevalonate kinase gene (MVK), encoding mevalonate kinase (MK) enzyme. MVK mutations have been reported as associated with impairment of mevalonate pathway with consequent decrease of protein prenylation levels, defective autophagy and increase of IL-1β secretion, followed by cell death. Since 25-hydroxycholesterol (25-HC), a metabolite of cholesterol, can suppress IL-1β production, thus reducing inflammation, we evaluated the effect of 25-HC in an in vitro model of mevalonate pathway alteration, obtained using Lovastatin. Human glioblastoma cell line (U87-MG) was chosen to mimic, at least in part, the central nervous system impairment observed in MKD; 25-HC effects were evaluated aimed at disclosing if this compound could be considered as novel potential drug for MKD. Our results showed that 25-HC is able to reduce inflammation but it is ineffective to restore autophagy flux and to decrease apoptosis levels, both caused by lower protein prenylation; so, in spite of its anti-inflammatory action it is not useful to rescue defective prenylation/autophagy impairment-driven apoptosis in Lovastatin impaired mevalonate pathway. We hypothesize the presence in the mevalonate pathway of alternative mechanisms acting between inflammation and apoptotic autophagy impairment.

UI MeSH Term Description Entries
D007249 Inflammation A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. Innate Inflammatory Response,Inflammations,Inflammatory Response, Innate,Innate Inflammatory Responses
D008148 Lovastatin A fungal metabolite isolated from cultures of Aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (HYDROXYMETHYLGLUTARYL COA REDUCTASES), which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. Lovastatin, 1 alpha-Isomer,Mevinolin,6-Methylcompactin,Lovastatin, (1 alpha(S*))-Isomer,MK-803,Mevacor,Monacolin K,1 alpha-Isomer Lovastatin,6 Methylcompactin,Lovastatin, 1 alpha Isomer,MK 803,MK803,alpha-Isomer Lovastatin, 1
D008798 Mevalonic Acid A dihydroxy monocarboxylic acid and precursor in the biosynthetic pathway known as the mevalonate pathway, which produces terpenes and steroids that are vital for diverse cellular functions. Mevalonate,Acid, Mevalonic
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006888 Hydroxycholesterols Cholesterol which is substituted by a hydroxy group in any position.
D001343 Autophagy The segregation and degradation of various cytoplasmic constituents via engulfment by MULTIVESICULAR BODIES; VACUOLES; or AUTOPHAGOSOMES and their digestion by LYSOSOMES. It plays an important role in BIOLOGICAL METAMORPHOSIS and in the removal of bone by OSTEOCLASTS. Defective autophagy is associated with various diseases, including NEURODEGENERATIVE DISEASES and cancer. Autophagocytosis,ER-Phagy,Lipophagy,Nucleophagy,Reticulophagy,Ribophagy,Autophagy, Cellular,Cellular Autophagy,ER Phagy
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D017209 Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, i.e., DNA FRAGMENTATION. It is genetically programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Apoptosis, Extrinsic Pathway,Apoptosis, Intrinsic Pathway,Caspase-Dependent Apoptosis,Classic Apoptosis,Classical Apoptosis,Programmed Cell Death,Programmed Cell Death, Type I,Apoptoses, Extrinsic Pathway,Apoptoses, Intrinsic Pathway,Apoptosis, Caspase-Dependent,Apoptosis, Classic,Apoptosis, Classical,Caspase Dependent Apoptosis,Cell Death, Programmed,Classic Apoptoses,Extrinsic Pathway Apoptoses,Extrinsic Pathway Apoptosis,Intrinsic Pathway Apoptoses,Intrinsic Pathway Apoptosis
D017368 Protein Prenylation A post-translational modification of proteins by the attachment of an isoprenoid to the C-terminal cysteine residue. The isoprenoids used, farnesyl diphosphate or geranylgeranyl diphosphate, are derived from the same biochemical pathway that produces cholesterol. Post-Translational Isoprenylation,Protein Isoprenylation,Protein Farnesylation,Protein Geranylgeranylation,Protein Polyisoprenylation,Farnesylation, Protein,Geranylgeranylation, Protein,Polyisoprenylation, Protein,Prenylation, Protein
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines

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