title: Very-low-density lipoprotein mediates transcriptional regulation of aldosterone synthase in human adrenocortical cells through multiple signaling pathways.
abstract: Diabetic dyslipidemia is characterized by increased circulatory very-low-density lipoprotein (VLDL) levels. Aldosterone, apart from its role in fluid and electrolyte homeostasis, has also been implicated in insulin resistance and myocardial fibrosis. The impact of VLDL as a potential risk factor for aldosterone-mediated cardiovascular injury in diabetes mellitus, however, remains to be investigated. We have therefore studied native and modified VLDL-mediated steroidogenesis and its underlying molecular mechanisms in human adrenocortical carcinoma cells, NCI H295R. Native VLDL (natVLDL), isolated from healthy volunteers, was subjected to in vitro modification with glucose (200 mmol/l) or sodium hypochlorite (1.5 mmol/l) for preparation of glycoxidized and oxidized VLDL, respectively. VLDL treatment induced steroidogenesis in both a concentration- and time-dependent manner. Native and glycoxidized VLDL (50 μg/ml) were almost two-fold more potent in adrenocortical aldosterone release than angiotensin II (100 nmol/l). These forms of VLDL significantly augmented transcriptional regulation of aldosterone synthase (Cyp11B2), partially through scavenger receptor class B type I, as evident from the effect of BLT-1. In contrast to glycoxidized VLDL, oxidized VLDL significantly attenuated the stimulatory effect of natVLDL on adrenocortical hormone synthesis. Moreover, treatment with specific pharmacological inhibitors (H89, U0126, AG490) provided supporting evidence that VLDL, irrespective of modification, presumably recruited PKA, ERK1/2 and Jak-2 for steroid hormone release through modulation of Cyp11B2 mRNA level. In conclusion, this study demonstrates a novel insight into intracellular mechanism of VLDL-mediated aldosterone synthesis through transcriptional regulation of steroidogenic acute regulatory protein (StAR) and Cyp11B2 expression in human adrenocortical carcinoma cell line.
authors.affiliation: Department of Internal Medicine III, Carl Gustav Carus Medical School, Technical University of Dresden, Dresden, Germany. Sarama.Saha@uniklinikum-dresden.de
authors.forename: Sarama
authors.initials: S
authors.lastname: Saha
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.forename: Juergen
authors.initials: J
authors.lastname: Graessler
authors.forename: Steffi
authors.initials: S
authors.lastname: Kopprasch
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism; D000450:Aldosterone / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D018955:CD36 Antigens; D008079:Lipoproteins, VLDL; D010750:Phosphoproteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000098682:Steroidogenic Acute Regulatory Protein; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases