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      Growth Hormone Increases Low-Density Lipoprotein Receptor and HMG-CoA Reductase mRNA Expression in Mesangial Cells

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          Abstract

          A dysregulation of the negative feedback mechanism of the low-density lipoprotein receptor (LDL-r) induced by hormones and cytokines may contribute to the development of glomerular injury and specifically could underlie growth hormone (GH)-induced glomerulosclerosis. The present study investigates the role of GH in the regulation of LDL-r and HMG-CoA reductase mRNA expression in mesangial cells. Mouse mesangial cells were equilibrated in a medium containing 5% lipoprotein-deprived serum (LPDS) for 48 h, prior to addition of GH (0.25 µ M). Transcript levels of LDL-r, HMG-CoA reductase and GH-receptor (GH-r) were measured at days 2 and 4 and intracellular lipid content was evaluated by oil red-O staining. The addition of GH significantly increased both the LDL-r and HMG-CoA reductase transcript levels at day 2 compared to control. Oil red-O positive staining increased following the initial period of 48 h lipoprotein deprivation, but addition of GH in a subsequent 48-hour period did not alter lipid content to a measurable degree compared with control. The present study demonstrates that GH significantly increased HMG-CoA reductase and LDL-r transcript levels in mesangial cells deprived of lipoproteins suggesting that abnormal levels of GH may play a role in glomerular lipid accumulation.

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          Most cited references 4

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          SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation.

          In liver, the synthesis of cholesterol and fatty acids increases in response to cholesterol deprivation and insulin elevation, respectively. This regulatory mechanism underlies the adaptation to cholesterol synthesis inhibitors (statins) and high calorie diets (insulin). In nonhepatic cells, lipid synthesis is controlled by sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors whose active domains are released proteolytically to enter the nucleus and activate genes involved in the synthesis and uptake of cholesterol and fatty acids. SCAP (SREBP cleavage-activating protein) is a sterol-regulated escort protein that transports SREBPs from their site of synthesis in the endoplasmic reticulum to their site of cleavage in the Golgi. Here, we produced a conditional deficiency of SCAP in mouse liver by genomic recombination mediated by inducible Cre recombinase. SCAP-deficient mice showed an 80% reduction in basal rates of cholesterol and fatty acid synthesis in liver, owing to decreases in mRNAs encoding multiple biosynthetic enzymes. Moreover, these mRNAs failed to increase normally in response to cholesterol deprivation produced by a cholesterol synthesis inhibitor and to insulin elevation produced by a fasting-refeeding protocol. These data provide in vivo evidence that SCAP and the SREBPs are required for hepatic lipid synthesis under basal and adaptive conditions.
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            SREBP-1 mediates activation of the low density lipoprotein receptor promoter by insulin and insulin-like growth factor-I.

            Transcription of the low density lipoprotein (LDL) receptor gene is regulated by intracellular cholesterol concentration, hormones, and growth factors. We studied the mechanisms by which insulin and estradiol stimulate promoter activity of the LDL receptor gene. Hormonal effects were analyzed in HepG2 cells after transient transfection with promotor reporter gene constructs. Successive 5' deletions of the LDL receptor promoter fragment from -537 to +88 revealed the sterol regulatory element 1 (SRE-1) between -65 and -56 as an insulin- and estradiol-sensitive cis-element. If the SRE-1 is point mutated at position -59 (C to G), which abolishes the binding of the SRE binding proteins (SREBP-1 and SREBP-2), no insulin or estradiol stimulatory effect on reporter gene expression was observed, indicating a role of SRE binding proteins in this regulatory mechanism. The concentration of the 125-kDa membrane-integrated SREBP-1 precursor protein in LDL repressed HepG2 cells is not altered by hormone treatment. Concentrations of SREBP-1 mRNA and precursor protein are reduced significantly by high and stable expression of an SREBP-1 antisense cDNA fragment in HepG2 cells (SREBP1(-) cells). Transfection of SREBP1(-) cells with promoter construct phLDL4 (-105 to +88) reduces induction of reporter gene activity by insulin and insulin-like growth factor-I to 35 and 17%, respectively, compared with HepG2 cells. The stimulatory effect of estradiol remains unchanged, and the inductions by pravastatin are enlarged. We conclude that different regulatory effects converge at SRE-1, but that SREBP-1 is selectively involved in the signal transduction pathway of insulin and insulin-like growth factor-I leading to LDL receptor gene activation.
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              Dysregulation of LDL receptor under the influence of inflammatory cytokines: a new pathway for foam cell formation.

              Lipid-mediated renal injury is an important component of glomerulosclerosis and its similarity to atherosclerosis is well described. This study focused on the relationship between lipid-mediated injury and inflammation by examining the role of inflammatory cytokines in the regulation of human mesangial cell low-density lipoprotein (LDL) receptors. A human mesangial cell line (HMCL) was used to study the effects of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) on the regulation of LDL receptor mRNA and protein in the presence of a high concentration of native LDL (250 microg/mL). Native LDL caused foam cell formation in HMCL in the presence of antioxidants, TNF-alpha and IL-1beta. Both cytokines overrode LDL receptor suppression induced by a high concentration of LDL and increased LDL uptake by enhancing receptor expression. These cytokines also caused increased expression of SCAP [sterol responsive element binding protein (SREBP) cleavage activation protein], and an increase in the nuclear translocation of SREBP, which induces LDL receptor expression. These observations demonstrate that inflammatory cytokines can modify cholesterol-mediated LDL receptor regulation in mesangial cells, permitting unregulated intracellular accumulation of unmodified LDL and causing foam cell formation. These findings suggest that inflammatory cytokines contribute to lipid-mediated renal damage, and also may have wider implications for the study of inflammation in the atherosclerotic process.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2003
                April 2003
                17 November 2004
                : 93
                : 4
                : e134-e140
                Affiliations
                aDepartment of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil; bUniformed Services University of the Health Sciences, Bethesda, Md., USA
                Article
                70237 Nephron Exp Nephrol 2003;93:e134–e140
                10.1159/000070237
                12759574
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 4, References: 39, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/70237
                Categories
                Original Paper

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