Signaling molecules derived from the cholesterol biosynthetic pathway: mechanisms of action and possible roles in human disease.

The association of high plasma cholesterol levels with the development of atherosclerosis is well known. The metabolic pathways that are regulated by cholesterol and the mechanisms involved are less well understood. Recent studies have identified not only cholesterol, but also oxysterols and isoprenoids, derived from the cholesterol biosynthetic pathway, as new signaling molecules. The transcriptional and post-transcriptional regulation of specific genes and metabolic pathways by these newly discovered signaling molecules may be important in the development of human disease and forms the topic of this review.

[1]  B. Spiegelman,et al.  Transcriptional Activation of the Stearoyl-CoA Desaturase 2 Gene by Sterol Regulatory Element-binding Protein/Adipocyte Determination and Differentiation Factor 1* , 1998, The Journal of Biological Chemistry.

[2]  P. Edwards,et al.  CBP Is Required for Sterol-regulated and Sterol Regulatory Element-binding Protein-regulated Transcription* , 1998, The Journal of Biological Chemistry.

[3]  P. Beachy,et al.  Teratogen-mediated inhibition of target tissue response to Shh signaling. , 1998, Science.

[4]  E. Strauss One-Eyed Animals Implicate Cholesterol in Development , 1998, Science.

[5]  S. Mellon,et al.  25-Hydroxycholesterol is not a ligand for the orphan nuclear receptor steroidogenic factor-1 (SF-1). , 1998, Endocrinology.

[6]  R. Hammer,et al.  Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2. , 1998, The Journal of clinical investigation.

[7]  R. Hammer,et al.  Cholesterol and Bile Acid Metabolism Are Impaired in Mice Lacking the Nuclear Oxysterol Receptor LXRα , 1998, Cell.

[8]  Andrew J. Bannister,et al.  The acetyltransferase activity of CBP stimulates transcription , 1998, The EMBO journal.

[9]  T. Osborne,et al.  Specificity in cholesterol regulation of gene expression by coevolution of sterol regulatory DNA element and its binding protein. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[10]  M. Krieger The "best" of cholesterols, the "worst" of cholesterols: a tale of two receptors. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[11]  B. Spiegelman,et al.  ADD1/SREBP1 activates PPARγ through the production of endogenous ligand , 1998 .

[12]  P. Edwards,et al.  Synergistic activation of transcription by nuclear factor Y and sterol regulatory element binding protein. , 1998, Journal of lipid research.

[13]  J. Goldstein,et al.  Cleavage of Sterol Regulatory Element-binding Proteins (SREBPs) at Site-1 Requires Interaction with SREBP Cleavage-activating Protein , 1998, The Journal of Biological Chemistry.

[14]  M. Harada‐Shiba,et al.  Oxidized Low Density Lipoprotein Induces Apoptosis in Cultured Human Umbilical Vein Endothelial Cells by Common and Unique Mechanisms* , 1998, The Journal of Biological Chemistry.

[15]  A. Diehl,et al.  Tumor necrosis factor-alpha stimulates the maturation of sterol regulatory element binding protein-1 in human hepatocytes through the action of neutral sphingomyelinase. , 1998, The Journal of biological chemistry.

[16]  P. Clayton Disorders of cholesterol biosynthesis , 1998, Archives of disease in childhood.

[17]  R. Currie NF-Y Is Associated with the Histone Acetyltransferases GCN5 and P/CAF* , 1998, The Journal of Biological Chemistry.

[18]  K. Dooley,et al.  Sterol Regulation of 3-Hydroxy-3-Methylglutaryl-coenzyme A Synthase Gene through a Direct Interaction Between Sterol Regulatory Element Binding Protein and the Trimeric CCAAT-binding Factor/Nuclear Factor Y* , 1998, The Journal of Biological Chemistry.

[19]  M. T. Hasan,et al.  Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs. , 1997, Molecular cell.

[20]  D. Lütjohann,et al.  Importance of a Novel Oxidative Mechanism for Elimination of Brain Cholesterol , 1997, The Journal of Biological Chemistry.

[21]  J. Swinnen,et al.  Coordinate regulation of lipogenic gene expression by androgens: evidence for a cascade mechanism involving sterol regulatory element binding proteins. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[22]  R. Hampton,et al.  Ubiquitin-mediated regulation of 3-hydroxy-3-methylglutaryl-CoA reductase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[23]  I. Björkhem,et al.  Elimination of Cholesterol in Macrophages and Endothelial Cells by the Sterol 27-Hydroxylase Mechanism , 1997, The Journal of Biological Chemistry.

[24]  R. Hammer,et al.  Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene. , 1997, The Journal of clinical investigation.

[25]  M. Brown,et al.  Sphingomyelin depletion in cultured cells blocks proteolysis of sterol regulatory element binding proteins at site 1. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Jasmine Chen,et al.  The orphan nuclear receptor LXRalpha is positively and negatively regulated by distinct products of mevalonate metabolism. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[27]  R. Lathe,et al.  Identification and Characterization of a Mouse Oxysterol 7α-Hydroxylase cDNA* , 1997, The Journal of Biological Chemistry.

[28]  R. D. Simoni,et al.  Farnesol as a regulator of HMG-CoA reductase degradation: characterization and role of farnesyl pyrophosphatase. , 1997, Archives of biochemistry and biophysics.

[29]  J. Goldstein,et al.  Identification of Complexes between the COOH-terminal Domains of Sterol Regulatory Element-binding Proteins (SREBPs) and SREBP Cleavage-Activating Protein* , 1997, The Journal of Biological Chemistry.

[30]  T. Osborne,et al.  Sterol regulation of acetyl coenzyme A carboxylase promoter requires two interdependent binding sites for sterol regulatory element binding proteins. , 1997, Journal of lipid research.

[31]  J. Lehmann,et al.  Activation of the orphan receptor RIP14 by retinoids. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[32]  W. Pavan,et al.  Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. , 1997, Science.

[33]  K. G. Coleman,et al.  Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. , 1997, Science.

[34]  A. Kuksis,et al.  Oxidation products of cholesteryl linoleate are resistant to hydrolysis in macrophages, form complexes with proteins, and are present in human atherosclerotic lesions. , 1997, Journal of lipid research.

[35]  Y. Masuda,et al.  Geranylgeraniol potently induces caspase-3-like activity during apoptosis in human leukemia U937 cells. , 1997, Biochemical and biophysical research communications.

[36]  D. Mangelsdorf,et al.  Activation of the orphan nuclear receptor steroidogenic factor 1 by oxysterols. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[37]  J. Goldstein,et al.  Cleavage Site for Sterol-regulated Protease Localized to a Leu-Ser Bond in the Lumenal Loop of Sterol Regulatory Element-binding Protein-2* , 1997, The Journal of Biological Chemistry.

[38]  J. Goldstein,et al.  The SREBP Pathway: Regulation of Cholesterol Metabolism by Proteolysis of a Membrane-Bound Transcription Factor , 1997, Cell.

[39]  A. Bist,et al.  Caveolin mRNA levels are up-regulated by free cholesterol and down-regulated by oxysterols in fibroblast monolayers. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Timothy F. Osborne,et al.  Multiple Sequence Elements are Involved in the Transcriptional Regulation of the Human Squalene Synthase Gene* , 1997, The Journal of Biological Chemistry.

[41]  P. Gambert,et al.  Evaluation of the cytotoxic effects of some oxysterols and of cholesterol on endothelial cell growth: methodological aspects. , 1997, Pathologie-biologie.

[42]  B. Spiegelman,et al.  Identification of Glycerol-3-phosphate Acyltransferase as an Adipocyte Determination and Differentiation Factor 1- and Sterol Regulatory Element-binding Protein-responsive Gene* , 1997, The Journal of Biological Chemistry.

[43]  R. Hammer,et al.  Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. , 1997, The Journal of clinical investigation.

[44]  I. Shimomura,et al.  Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells. , 1997, The Journal of clinical investigation.

[45]  Timothy M. Willson,et al.  Activation of the Nuclear Receptor LXR by Oxysterols Defines a New Hormone Response Pathway* , 1997, The Journal of Biological Chemistry.

[46]  O. Wiklund,et al.  Macrophages isolated from human atherosclerotic plaques produce IL-8, and oxysterols may have a regulatory function for IL-8 production. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[47]  T. Osborne,et al.  Two Tandem Binding Sites for Sterol Regulatory Element Binding Proteins Are Required for Sterol Regulation of Fatty-acid Synthase Promoter* , 1996, The Journal of Biological Chemistry.

[48]  A. Tall,et al.  Human Cholesteryl Ester Transfer Protein Gene Proximal Promoter Contains Dietary Cholesterol Positive Responsive Elements and Mediates Expression in Small Intestine and Periphery While Predominant Liver and Spleen Expression Is Controlled by 5′-distal Sequences , 1996, The Journal of Biological Chemistry.

[49]  J. Rine,et al.  Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein. , 1996, Molecular biology of the cell.

[50]  Jonathan D. Smith,et al.  Cyclic AMP Induces Apolipoprotein E Binding Activity and Promotes Cholesterol Efflux from a Macrophage Cell Line to Apolipoprotein Acceptors* , 1996, The Journal of Biological Chemistry.

[51]  R. Tjian,et al.  SREBP transcriptional activity is mediated through an interaction with the CREB-binding protein. , 1996, Genes & development.

[52]  X. Hua,et al.  Sterol Resistance in CHO Cells Traced to Point Mutation in SREBP Cleavage–Activating Protein , 1996, Cell.

[53]  Tatsuhiko Kodama,et al.  Sterol-dependent Transcriptional Regulation of Sterol Regulatory Element-binding Protein-2* , 1996, The Journal of Biological Chemistry.

[54]  D. Mangelsdorf,et al.  An oxysterol signalling pathway mediated by the nuclear receptor LXRα , 1996, Nature.

[55]  P. Beachy,et al.  Cholesterol Modification of Hedgehog Signaling Proteins in Animal Development , 1996, Science.

[56]  S. Ōmura,et al.  Degradation of 3-Hydroxy-3-methylglutaryl-CoA Reductase in Endoplasmic Reticulum Membranes Is Accelerated as a Result of Increased Susceptibility to Proteolysis* , 1996, The Journal of Biological Chemistry.

[57]  R. Hammer,et al.  Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. , 1996, The Journal of clinical investigation.

[58]  G. Chisolm,et al.  Roles of multiple oxidized LDL lipids in cellular injury: dominance of 7 beta-hydroperoxycholesterol. , 1996, Journal of lipid research.

[59]  S. Kitareewan,et al.  Phytol metabolites are circulating dietary factors that activate the nuclear receptor RXR. , 1996, Molecular biology of the cell.

[60]  X. Hua,et al.  Sterol-Regulated Release of SREBP-2 from Cell Membranes Requires Two Sequential Cleavages, One Within a Transmembrane Segment , 1996, Cell.

[61]  K. Suckling,et al.  The Novel Cholesterol-lowering Drug SR-12813 Inhibits Cholesterol Synthesis via an Increased Degradation of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase* , 1996, The Journal of Biological Chemistry.

[62]  B. Spiegelman,et al.  ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. , 1996, Genes & development.

[63]  J. Capone,et al.  The Orphan Nuclear Hormone Receptor LXR Interacts with the Peroxisome Proliferator-activated Receptor and Inhibits Peroxisome Proliferator Signaling (*) , 1996, The Journal of Biological Chemistry.

[64]  A. Tall,et al.  Interleukin 8 Is Induced by Cholesterol Loading of Macrophages and Expressed by Macrophage Foam Cells in Human Atheroma (*) , 1996, The Journal of Biological Chemistry.

[65]  R. D. Simoni,et al.  Regulation of 3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase Degradation by the Nonsterol Mevalonate Metabolite Farnesol in Vivo(*) , 1996, The Journal of Biological Chemistry.

[66]  G. Schmitz,et al.  Genetic and biochemical evidence that CESD and Wolman disease are distinguished by residual lysosomal acid lipase activity. , 1996, Genomics.

[67]  J. Vilček,et al.  CCAAT Box Enhancer Binding Protein (C/EBP-) Stimulates B Element-mediated Transcription in Transfected Cells (*) , 1996, The Journal of Biological Chemistry.

[68]  P. Edwards,et al.  Sterol regulatory element binding protein binds to a cis element in the promoter of the farnesyl diphosphate synthase gene. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[69]  D. Hajjar,et al.  Cholesterol enrichment enhances expression of sterol-carrier protein-2: implications for its function in intracellular cholesterol trafficking. , 1995, Journal of lipid research.

[70]  Jasmine Chen,et al.  Identification of a nuclear receptor that is activated by farnesol metabolites , 1995, Cell.

[71]  K. Umesono,et al.  LXR, a nuclear receptor that defines a distinct retinoid response pathway. , 1995, Genes & development.

[72]  B. Spiegelman,et al.  Dual DNA binding specificity of ADD1/SREBP1 controlled by a single amino acid in the basic helix-loop-helix domain , 1995, Molecular and cellular biology.

[73]  M. Brown,et al.  Independent regulation of sterol regulatory element-binding proteins 1 and 2 in hamster liver. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[74]  J. Hoeg,et al.  Identification of novel differentially expressed hepatic genes in cholesterol-fed rabbits by a non-targeted gene approach. , 1995, Journal of lipid research.

[75]  P. Edwards,et al.  Identification of farnesol as the non-sterol derivative of mevalonic acid required for the accelerated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. , 1994, The Journal of biological chemistry.

[76]  X. Hua,et al.  SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis , 1994, Cell.

[77]  G Salen,et al.  Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. , 1994, The New England journal of medicine.

[78]  P. Edwards,et al.  Mevalonic acid-dependent degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in vivo and in vitro. , 1994, The Journal of biological chemistry.

[79]  B. Spiegelman,et al.  ADD1: a novel helix-loop-helix transcription factor associated with adipocyte determination and differentiation , 1993, Molecular and cellular biology.

[80]  G. Chisolm Cytotoxicity of oxidized lipoproteins , 1991 .

[81]  B. Spiegelman,et al.  Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1. , 1998, The Journal of clinical investigation.

[82]  J. Cooper,et al.  Mutational analysis of capping protein function in Saccharomyces cerevisiae. , 1996, Molecular biology of the cell.

[83]  D. Moore,et al.  Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors. , 1995, Molecular endocrinology.