alitretinoin and mevalonolactone

We studied the effects of cholesterol, its oxidized derivatives mevalonate, and nuclear receptor agonists LXR, RXR, and FXR on the production of transforming growth factor-beta1 (TGF- beta1) by macrophages. After recruiting of macrophage monocytes into the focus of inflammation, the production of TGF-beta1 increased by 3.5 times in comparison with control macrophages. Cholesterol diet stimulated the production of TGF-beta1 by 2.5 times. Cholesterol directly stimulated macrophage production of TGF-beta1 in vitro, while addition of mevalonate to the incubation medium effectively reduced this induced production. Agonists of nuclear receptor sharply reduced the production of TGF-beta1 in recruited macrophages. Under conditions of inflammation, hypercholesterolemia can be a factor of fibrogenesis due to TGF-beta1 induction in macrophages, which depends on the products of mevalonate biochemical chain.

Topics: Alitretinoin; Animals; Cells, Cultured; Cholesterol; Farnesol; Hydroxycholesterols; Hydroxysteroids; Ketocholesterols; Lipopolysaccharides; Liver X Receptors; Macrophages; Male; Mevalonic Acid; Mice; Mice, Inbred C57BL; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear; Retinoid X Receptors; Transforming Growth Factor beta; Tretinoin

Neural apoptosis-regulated convertase (NARC)-1 is the newest member of the proprotein convertase family implicated in the cleavage of a variety of protein precursors. The NARC-1 gene, PCSK9, has been identified recently as the third locus implicated in autosomal dominant hypercholesterolemia (ADH). The 2 other known genes implicated in ADH encode the low-density lipoprotein receptor and apolipoprotein B. As an approach toward the elucidation of the physiological role(s) of NARC-1, we studied its transcriptional regulation.. Using quantitative RT-PCR, we assessed NARC-1 regulation under conditions known to regulate genes involved in cholesterol metabolism in HepG2 cells and in human primary hepatocytes. We found that NARC-1 expression was strongly induced by statins in a dose-dependent manner and that this induction was efficiently reversed by mevalonate. NARC-1 mRNA level was increased by cholesterol depletion but insensitive to liver X receptor activation. Human, mouse, and rat PCSK9 promoters contain 2 typical conserved motifs for cholesterol regulation: a sterol regulatory element (SRE) and an Sp1 site.. PCSK9 regulation is typical of that of the genes implicated in lipoprotein metabolism. In vivo, PCSK9 is probably a target of SRE-binding protein (SREBP)-2.

Topics: Alitretinoin; Animals; Atorvastatin; Base Sequence; Cell Line; Cholesterol; Consensus Sequence; DNA-Binding Proteins; Gene Expression Regulation; Hepatocytes; Heptanoic Acids; Homeostasis; Humans; Hydroxycholesterols; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver X Receptors; Lovastatin; Mevalonic Acid; Mice; Orphan Nuclear Receptors; Promoter Regions, Genetic; Proprotein Convertase 9; Proprotein Convertases; Pyridines; Pyrroles; Quinolines; Rats; Receptors, Cytoplasmic and Nuclear; Regulatory Sequences, Nucleic Acid; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sequence Alignment; Sequence Homology, Nucleic Acid; Serine Endopeptidases; Simvastatin; Sp1 Transcription Factor; Species Specificity; Sterol Regulatory Element Binding Protein 2; Transcription Factors; Tretinoin