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Cholesterol: from feeding to gene regulation

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Abstract

We present here a brief description of the path that cholesterol covers from its intestinal absorption to its effects exerted on gene regulation. In particular, the relationship between cholesterol and the protein complexes involved in the intricate gene regulation mechanism implicated in cholesterol homeostasis will be discussed. In addition, a new target role for the pharmacological interventions of one of these factors, the insulin-induced gene (Insig) protein, will be introduced.

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Abbreviations

HMG-CoAR:

3-Hydroxy-3-methylglutaryl coenzyme A reductase

HMG-CoAS:

3-Hydroxy-3-methylglutaryl coenzyme A synthase

PGDH:

6-Phosphogluconate dehydrogenase

DHCR:

7-Dehydrocholesterol reductase

ACC:

Acetyl-CoA carboxylase

ACAT:

Acyl-CoA:cholesterol acyltransferase

aa:

Amino acid

APP:

Amyloid peptide

Apo:

Apoprotein

ABC:

ATP binding cassette

bHLH-Lzip:

Basic-helix–loop–helix-leucine zipper

CMs:

Chylomicrons

Cyp7α:

Cholesterol 7α hydroxylase

CETP:

Cholesteryl ester transfer protein

CBP:

CREB binding protein

ADD1:

Determination and differentiation factor 1

ERC:

Endocytic recycling compartment

ER:

Endoplasmic reticulum

FPP:

Farnesyl diphosphate

FAS:

Fatty acid synthase

GPP:

Geranylgeranyl pyrophosphate synthase

GPAT:

Glycerol-3-phosphate acyltransferase

G6PD:

Glucose-6-phosphate dehydrogenase

HDL:

High-density lipoprotein

Insig:

Insulin-induced gene

CY51:

Lanosterol 14α-demethylase

LPL:

Lipoprotein lipase

LXR:

Liver X receptor

LDL:

Low-density lipoprotein

LDLr:

Low-density lipoprotein receptors

MAPK:

Mitogen-activated protein kinase

ALLN:

N-Acetyl-l-leucyl-l-leucyl-norleucinal

NPC1L1:

Nieman-Pick C1-like protein1

nSREBP:

Nuclear SREBP

PI(3)-kinase:

Phosphatidyl inositol (3) kinase

PM:

Plasma membrane

PKB:

Protein kinase B

PKCk:

Protein kinase Ck

SR-B1:

Scavenger receptor class B type 1

SCAP:

SREBP cleavage activating protein

S1P:

Site 1 protease

S2P:

Site 2 protease

SUMO–1:

Small ubiquitin-related modifier-1

SCD:

Stearoyl-CoA desaturase

SSD:

Sterol sensing domain

SRE:

Sterol regulatory element

SREBPs:

Sterol regulatory binding proteins

S f :

Svedberg flotation

TG:

Triglyceride

VLDL:

Very low-density lipoprotein

DRIP:

Vitamin D receptor-integrating protein

WAT:

White adipose tissue

References

  1. Adams CM, Goldstein JL, Brown MS (2003) Cholesterol induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles. Proc Natl Acad Sci USA 100:10647–10652

    PubMed  CAS  Google Scholar 

  2. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002) Molecular biology of the cell. Garland Science, New York

    Google Scholar 

  3. Altmann SW, Davis HR Jr, Zhu LJ, Yao X, Hoos LM, Tetzloff G, Iyer SP, Maguire M, Golovko A, Zeng M, Wang L, Murgolo N, Graziano MP (2004) Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol absorption. Science 303:1201–1204

    PubMed  CAS  Google Scholar 

  4. Amemiya-Kudo M, Shimano H, Yoshikawa T, Yahagi N, Hasty AH, Okazaki H, Tamura Y, Shionoiri F, Iizuka Y, Ohashi K, Osuga J, Harada K, Gotoda T, Sato R, Kimura S, Ishibashi S, Yamada N (2000) Promoter analysis of the mouse sterol regulatory element binding protein-1c gene. J Biol Chem 275:31078–31085

    PubMed  CAS  Google Scholar 

  5. Antonny B, Schekman R (2001) ER export: public transportation by the COPII coach. Curr Opin Cell Biol 13:438–443

    PubMed  CAS  Google Scholar 

  6. Aridor M, Weissman J, Bannykh SI, Nuoffer C, Balch WE (1998) Cargo selection by the COPII budding machinery during export from the ER. J Cell Biol 141:61–70

    PubMed  CAS  Google Scholar 

  7. Azzout-Marniche D, Becard D, Guichard C, Foretz M, Ferre P, Foufelle F (2000) Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes. Biochem J 350(Pt. 2):389–393

    PubMed  CAS  Google Scholar 

  8. Barlowe C (2002) COPII-dependent transport from the endoplasmic reticulum. Curr Opin Cell Biol 14:417–422

    PubMed  CAS  Google Scholar 

  9. Bizeau ME, MacLean PS, Johnson GC, Wei Y (2003) Skeletal muscle sterol regulatory element binding protein-1c decreases with food deprivation and increases with feeding in rats. J Nutr 133:1787–1792

    PubMed  CAS  Google Scholar 

  10. Bose C, Bhuvaneswaran C, Udupa KB (2005) Age-related alteration in hepatic acyl-CoA: cholesterol acyltransferase and its relation to LDL receptor and MAPK. Mech Ageing Dev 126:740–751

    PubMed  CAS  Google Scholar 

  11. Bosner MS, Lange LG, Stenson WF, Ostlund RE Jr (1999) Percent cholesterol absorption in normal women and men quantified with dual stable isotopic tracers and negative ion mass spectrometry. J Lipid Res 40:302–308

    PubMed  CAS  Google Scholar 

  12. Brown MS, Goldstein JL (1986) A receptor mediated pathway for cholesterol homeostasis. Science 232:24–47

    Google Scholar 

  13. Brown MS, Goldstein JL (1997) The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89:331–340

    PubMed  CAS  Google Scholar 

  14. Brown MS, Goldstein JL (1999) A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci USA 96:11041–11048

    PubMed  CAS  Google Scholar 

  15. Brown MS, Ye J, Rawson RB, Goldstein JL (2000) Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100:391–398

    PubMed  CAS  Google Scholar 

  16. Buhman KK, Accad M, Novak S, Choi RS, Wong JS, Hamilton RL, Turley S, Farese RV Jr (2000) Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nat Med 6:1341–1347

    PubMed  CAS  Google Scholar 

  17. Chen IS, Hotta SS, Ikeda I, Cassidy MM, Sheppard AJ, Vahouny GV (1987) Digestion, absorption and effects on cholesterol absorption of menhaden oil, fish oil concentrate and corn oil by rats. J Nutr 117:1676–1680

    PubMed  CAS  Google Scholar 

  18. Commerford SR, Peng L, Dube JJ, O’Doherty RM (2004) In vivo regulation of SREBP-1c in skeletal muscle: effects of nutritional status, glucose, insulin, and leptin. Am J Physiol Regul Integr Comp Physiol 287:R218–R227

    PubMed  CAS  Google Scholar 

  19. Dietschy JM, Turley SD, Spady DK (1993) Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res 34:1637–1659

    PubMed  CAS  Google Scholar 

  20. Distefano E, Marino M, Gillette JA, Hanstein B, Pallottini V, Bruning J, Krone W, Trentalance A (2002) Role of tyrosine kinase signaling in estrogen-induced LDL receptor gene expression in HepG2 cells. Biochim Biophys Acta 1580:145–149

    PubMed  CAS  Google Scholar 

  21. Duncan EA, Brown MS, Goldstein JL, Sakai J (1997) Cleavage site for sterol-regulated protease localized to a leu-Ser bond in the luminal loop of sterol regulatory element-binding protein-2. J Biol Chem 272:12778–12785

    PubMed  CAS  Google Scholar 

  22. Duncan EA, Dave UP, Sakai J, Goldstein JL, Brown MS (1998) Second-site cleavage in sterol regulatory element-binding protein occurs at transmembrane junction as determined by cysteine panning. J Biol Chem 273:17801–17809

    PubMed  CAS  Google Scholar 

  23. Eckhardt ER, Wang DQ, Donovan JM, Carey MC (2002) Dietary sphingomyelin suppresses intestinal cholesterol absorption by decreasing thermodynamic activity of cholesterol monomers. Gastroenterology 122:948–956

    PubMed  CAS  Google Scholar 

  24. Einarsson K, Nilsell K, Leijd B, Angelin B (1985) Influence of age on secretion of cholesterol and synthesis of bile acids by the liver. N Engl J Med 313:277–282

    Article  PubMed  CAS  Google Scholar 

  25. Epand RM (2006) Cholesterol and the interaction of proteins with membrane domains. Prog Lipid Res 45:279–294

    PubMed  CAS  Google Scholar 

  26. Espenshade PJ, Cheng D, Goldstein JL, Brown MS (1999) Autocatalytic processing of site-1 protease removes propeptide and permits cleavage of sterol regulatory element-binding proteins. J Biol Chem 274:22795–22804

    PubMed  CAS  Google Scholar 

  27. Espenshade PJ, Li WP, Yabe D (2002) Sterols block binding of COPII proteins to SCAP, thereby controlling SCAP sorting in ER. Proc Natl Acad Sci USA 99:11694–11699

    PubMed  CAS  Google Scholar 

  28. Feramisco JD, Goldstein JL, Brown MS (2004) Membrane topology of human insig-1, a protein regulator of lipid synthesis. J Biol Chem 279:8487–8496

    PubMed  CAS  Google Scholar 

  29. Fleischmann M, Iynedjian PB (2000) Regulation of sterol regulatory element binding protein 1 gene expression in liver: role of insulin and protein kinase B/cAkt. Biochem J 349:13–17

    PubMed  CAS  Google Scholar 

  30. Foretz M, Guichard C, Ferre P, Foufelle F (1999a) Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. Proc Natl Acad Sci USA 96:12737–12774

    PubMed  CAS  Google Scholar 

  31. Foretz M, Pacot C, Dugail I, Lemarchand P, Guichard C, Le Liepvre X, Berthelier-Lubrano C, Spiegelman B, Kim JB, Ferre P, Foufelle F (1999b) ADD1/SREBP-1c is required in the activation of hepatic lipogenic gene expression by glucose. Mol Cell Biol 19:3760–3768

    PubMed  CAS  Google Scholar 

  32. Fulop T, Larbi A, Douziech N (2003) Insulin receptor and ageing. Pathol Biol (Paris) 51:574–580

    CAS  Google Scholar 

  33. Goldstein JL, Brown MS (1990) Regulation of the mevalonate pathway. Nature 343:425–430

    PubMed  CAS  Google Scholar 

  34. Goldstein JL, DeBose-Boyd RA, Brown MS (2006) Protein sensors for membrane sterols. Cell 124:35–46

    PubMed  CAS  Google Scholar 

  35. Gong Y, Lee JN, Lee PCW, Goldstein JL, Brown MS, Ye J (2006) Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake. Cell Metab 3:15–24

    PubMed  CAS  Google Scholar 

  36. Hegarty BD, Bobard A, Hainault I, Ferre P, Bossard P, Foufelle F (2005) Distinct roles of insulin and liver X receptor in the induction and cleavage of sterol regulatory element-binding protein-1c. Proc Natl Acad Sci USA 102:791–796

    PubMed  CAS  Google Scholar 

  37. Heider JG, Pickens CE, Kelly LA (1983) Role of acyl CoA:cholesterol acyltransferase in cholesterol absorption and its inhibition by 57–118 in the rabbit. J Lipid Res 24:1127–1134

    PubMed  CAS  Google Scholar 

  38. Henriksson P, Einarsson K, Eriksson A, Kelter U, Angelin B (1989) Estrogen-induced gallstone formation in males. Relation to changes in serum and biliary lipids during hormonal treatment of prostatic carcinoma. J Clin Invest 84:811–816

    PubMed  CAS  Google Scholar 

  39. Hirano Y, Murata S, Tanaka K, Shimizu M, Sato R (2003) Sterol regulatory element-binding proteins are negatively regulated through SUMO-1 modification independent of the ubiquitin/26 S proteasome pathway. J Biol Chem 278:16809–16819

    PubMed  CAS  Google Scholar 

  40. Hirano Y, Yoshida M, Shimizu M, Sato R (2001) Direct demonstration of rapid degradation of nuclear sterol regulatory element-binding proteins by the ubiquitin-proteasome pathway. J Biol Chem 276:36431–36437

    PubMed  CAS  Google Scholar 

  41. Hoffmann AF, Borgstrom B (1963) Hydrolysis of long-chain monoglycerides in micellar solution by pancreatic lipase. Biochim Biophys Acta 70:317–331

    Google Scholar 

  42. Horton JD, Bashmakov Y, Shimomura I, Shimano H (1998) Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice. Proc Natl Acad Sci USA 95:5987–5992

    PubMed  CAS  Google Scholar 

  43. Horton JD, Goldstein JL, Brown MS (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109:1125–1131

    PubMed  CAS  Google Scholar 

  44. Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS, Goldstein JL (2003a) Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci USA 100:12027–12032

    PubMed  CAS  Google Scholar 

  45. Horton JD, Shimomura I, Ikemoto S, Bashmakov Y, Hammer RE (2003b) Overexpression of SREBP-1a in mouse adipose tissue produces adipocyte hypertrophy, increased fatty acid secretion, and fatty liver. J Biol Chem 278:36652–36660

    PubMed  CAS  Google Scholar 

  46. Hua X, Nohturfft A, Goldstein JL, Brown MS (1996) Sterol resistance in CHO cells traced to point mutation in SREBP cleavage activating protein (SCAP). Cell 87:415–426

    PubMed  CAS  Google Scholar 

  47. Hua X, Sakai J, Ho YK, Goldstein JL, Brown MS (1995) Hairpin orientation of sterol regulatory element-binding protein-2 in cell membranes as determined by protease protection. J Biol Chem 270:29422–29427

    PubMed  CAS  Google Scholar 

  48. Hua X, Wu J, Goldstein JL, Brown MS, Hobbs HH (1995) Structure of the human gene encoding sterol regulatory element binding protein-1 (SREBF1) and localization of SREBF1 and SREBF2 to chromosomes 17p11.2 and 22q13. Genomics 25:667–673

    PubMed  CAS  Google Scholar 

  49. Hussain MM (2000) A proposed model for the assembly of chylomicrons. Atherosclerosis 148:1–15

    PubMed  CAS  Google Scholar 

  50. Ikeda I, Tanaka K, Sugano M, Vahouny GV, Gallo LL (1988) Inhibition of cholesterol absorption in rats by plant sterols. J Lipid Res 29:1573–1582

    PubMed  CAS  Google Scholar 

  51. Iynedjian PB, Roth RA, Fleischmann M, Gjinovci A (2000) Activation of protein kinase B/cAkt in hepatocytes is sufficient for the induction of expression of the gene encoding glucokinase. Biochem J 351(Pt. 3):621–627

    PubMed  CAS  Google Scholar 

  52. Janowski BA (2002) The hypocholesterolemic agent LY295427 upregulates INSIG-1, identifying the INSIG-1 protein as a mediator of cholesterol homeostasis through SREBP. Proc Natl Acad Sci USA 99:12675–12680

    PubMed  CAS  Google Scholar 

  53. Janowski BA, Grogan MJ, Jones SA, Wisely GB, Kliewer SA, Corey EJ, Mangelsdorf DJ (1999) Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. Proc Natl Acad Sci USA 96:266–271

    PubMed  CAS  Google Scholar 

  54. Kam NT, Albright E, Mathur S, Field FJ (1990) Effect of lovastatin on acyl-CoA: cholesterol O-acyltransferase (ACAT) activity and the basolateral-membrane secretion of newly synthesized lipids by CaCo-2 cells. Biochem J 272:427–433

    PubMed  CAS  Google Scholar 

  55. Kam NT, Albright E, Mathur SN, Field FJ (1989) Inhibition of acylcoenzyme A: cholesterol acyltransferase activity in CaCo-2 cells results in intracellular triglyceride accumulation. J Lipid Res 30:371–377

    PubMed  CAS  Google Scholar 

  56. Kim JB, Sarraf P, Wright M, Yao KM, Mueller E, Solanes G, Lowell BB, Spiegelman BM (1998) Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1. J Clin Invest 101:1–9

    PubMed  CAS  Google Scholar 

  57. Kim JB, Spotts GD, Halvorsen YD, Shih HM, Ellenberger T, Towle HC, Spiegelman BM (1995) Dual DNA binding specificity of ADD1/SREBP1 controlled by a single amino acid in the basic helix–loop–helix domain. Mol Cell Biol 15:2582–2588

    PubMed  CAS  Google Scholar 

  58. Kotzka J, Lehr S, Roth G, Avci H, Knebel B, Muller-Wieland D (2004) Insulin-activated Erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo. J Biol Chem 279:22404–22411

    PubMed  CAS  Google Scholar 

  59. Lammert F, Wang DQ (2005) New insights into the genetic regulation of intestinal cholesterol absorption. Gastroenterology 129:718–734

    PubMed  Google Scholar 

  60. Lee YS, Lee HH, Park J, Yoo EJ, Glackin CA, Choi YI, Jeon SH, Seong RH, Park SD, Kim JB (2003) Twist2, a novel ADD1/SREBP1c interacting protein, represses the transcriptional activity of ADD1/SREBP1c. Nucleic Acids Res 31:7165–7174

    PubMed  CAS  Google Scholar 

  61. Lee JN, Ye J (2004) Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1. J Biol Chem 279:45257–45265

    PubMed  CAS  Google Scholar 

  62. Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, Willson TM (1997) Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 272:3137–3140

    PubMed  CAS  Google Scholar 

  63. Lindgren FT, Jensen LC, Wills RD, Stevens GR (1972) Subfractionation of S f 4–10 5, S f 4–20 and high density lipoproteins. Lipids 7:194–201

    PubMed  CAS  Google Scholar 

  64. Luong A (2000) Identification of three novel SREBP-activated target genes: acetyl CoA synthetase, 3-β-hydroxysterol dehydrogenase, and CL-6/INSIG1. PhD dissertation. University of Texas Southwestern Medical Center at Dallas, Dallas, pp 1–137

  65. Magana MM, Koo SH, Towle HC, Osborne TF (2000) Different sterol regulatory element-binding protein-1 isoforms utilize distinct co-regulatory factors to activate the promoter for fatty acid synthase. J Biol Chem 275:4726–4733

    PubMed  CAS  Google Scholar 

  66. Masoro EJ (2005) Overview of caloric restriction and ageing. Mech Ageing Dev 126:913–22

    PubMed  CAS  Google Scholar 

  67. Matsumoto M, Ogawa W, Akimoto K, Inoue H, Miyake K, Furukawa K, Hayashi Y, Iguchi H, Matsuki Y, Hiramatsu R, Shimano H, Yamada N, Ohno S, Kasuga M, Noda T (2003) PKClambda in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity. J Clin Invest 112:935–944

    PubMed  CAS  Google Scholar 

  68. Messa C, Notarnicola M, Russo F, Cavallini A, Pallottini V, Trentalance A, Bifulco M, Laezza C, Caruso GM (2005) Estrogenic regulation of cholesterol biosynthesis and cell growth in DLD-1 human colon cancer cells. Scand J Gastroenterol 40:1454–1461

    PubMed  CAS  Google Scholar 

  69. Miserez AR, Cao G, Probst LC, Hobbs HH (1997) Structure of the human gene encoding sterol regulatory element binding protein 2 (SREBF2). Genomics 40:31–40

    PubMed  CAS  Google Scholar 

  70. Mohn KL, Laz TM, Hsu J-C, Melby AE, Bravo R, Taub R (1991) The immediate-early growth response in regenerating liver and insulin-stimulated H-35 cells: comparison with serum-stimulated 3T3 cells and identification of 41 novel immediate-early genes. Mol Cell Biol 11:381–390

    PubMed  CAS  Google Scholar 

  71. Moller N, Gormsen L, Fuglsang J, Gjedsted J (2003) Effects of ageing on insulin secretion and action. Horm Res 60:102–104

    PubMed  CAS  Google Scholar 

  72. Moon YA, Lee JJ, Park SW, Ahn YH, Kim KS (2000) The roles of sterol regulatory element-binding proteins in the transactivation of the rat ATP citrate-lyase promoter. J Biol Chem 275:30280–30286

    PubMed  CAS  Google Scholar 

  73. Moon YA, Shah NA, Mohapatra S, Warrington JA, Horton JD (2001) Identification of a mammalian long chain fatty acyl elongase regulated by sterol regulatory element-binding proteins. J Biol Chem 276:45358–45366

    PubMed  CAS  Google Scholar 

  74. Murthy S, Albright E, Mathur SN, Field FJ (1990) Effect of eicosapentaenoic acid on triacylglycerol transport in CaCo-2 cells. Biochim Biophys Acta 1045:147–155

    PubMed  CAS  Google Scholar 

  75. Murthy S, Albright E, Mathur SN, Davidson NO, Field FJ (1992) Apolipoprotein B mRNA abundance is decreased by eicosapentaenoic acid in CaCo-2 cells. Effect on the synthesis and secretion of apolipoprotein B. Arterioscler Thromb 12:691–700

    PubMed  CAS  Google Scholar 

  76. Naar AM, Beaurang PA, Robinson KM, Oliner JD, Avizonis D, Scheek S, Zwicker J, Kadonaga JT, Tjian R (1998) Chromatin, TAFs, and a novel multiprotein coactivator are required for synergistic activation by Sp1 and SREBP-1a in vitro. Genes Dev 12:3020–3031

    PubMed  CAS  Google Scholar 

  77. Naar AM, Beaurang PA, Zhou S, Abraham S, Solomon W, Tjian R (1999) Composite co-activator ARC mediates chromatin-directed transcriptional activation. Nature 398:828–832

    PubMed  CAS  Google Scholar 

  78. Nagoshi E, Yoneda Y (2001) Dimerization of sterol regulatory element-binding protein 2 via the helix–loop–helix-leucine zipper domain is a prerequisite for its nuclear localization mediated by importin beta. Mol Cell Biol 21:2779–2789

    PubMed  CAS  Google Scholar 

  79. Nagoshi E, Immoto N, Sato R, Yoneda Y (1999) Nuclear import of sterol regulatory element-binding protein-2, a basic helix–loop–helix-leucine zipper (bHLH-Zip)-containing transcription factor, occurs through the direct interaction of importin beta with HLH-Zip. Mol Biol Cell 10:2221–2233

    PubMed  CAS  Google Scholar 

  80. Ness GC, Lopez D (1995) Transcriptional regulation of rat hepatic low-density lipoprotein receptor and cholesterol 7 alpha hydroxylase by thyroid hormone. Arch Biochem Biophys 323:404–408

    PubMed  CAS  Google Scholar 

  81. Neufeld EB, Cooney AM, Pitha J, Dawidowicz EA, Dwyer NK, Pentchev PG, Blanchette-Mackie EJ (1996) Intracellular trafficking of cholesterol monitored with a cyclodextrin. J Biol Chem 271:21604–21613

    PubMed  CAS  Google Scholar 

  82. Nguyen TT (1999) The cholesterol-lowering action of plant stanol esters. J Nutr 129:2109–2112

    PubMed  CAS  Google Scholar 

  83. Nielsen LB, Stender S, Kjeldsen K (1993) Effect of lovastatin on cholesterol absorption in cholesterol-fed rabbits. Pharmacol Toxicol 72:148–151

    Article  PubMed  CAS  Google Scholar 

  84. Nohturfft A, Brown MS, Goldstein JL (1998a) Sterols regulate processing of carbohydrate chains of wild-type SREBP cleavageactivating protein (SCAP), but not sterol-resistant mutants Y298C or D443N. Proc Natl Acad Sci USA 95:12848–12853

    PubMed  CAS  Google Scholar 

  85. Nohturfft A, Brown MS, Goldstein JL (1998b) Topology of SREBP cleavage-activating protein, a polytopic membrane protein with a sterol-sensing domain. J Biol Chem 273:17243–17250

    PubMed  CAS  Google Scholar 

  86. Nohturfft A, Yabe D, Goldstein JL, Brown MS, Espenshade PJ (2000) Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes. Cell 102:315–323

    PubMed  CAS  Google Scholar 

  87. Ockner RK, Manning JA (1974) Fatty acid-binding protein in small intestine. Identification, isolation, and evidence for its role in cellular fatty acid transport. J Clin Invest 54:326–338

    PubMed  CAS  Google Scholar 

  88. Ockner RK, Hughes FB, Isselbacher KJ (1969) Very low density lipoproteins in intestinal lymph: role in triglyceride and cholesterol transport during fat absorption. J Clin Invest 48:2367–2373

    PubMed  CAS  Google Scholar 

  89. Oram JF, Heinecke JW (2005) ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease. Physiol Rev 85:1343–1372

    PubMed  CAS  Google Scholar 

  90. Osborne TF (2000) Sterol regulatory element-binding proteins (SREBPs): key regulators of nutritional homeostasis and insulin action. J Biol Chem 275:32379–32382

    PubMed  CAS  Google Scholar 

  91. Ostlund RE Jr, Racette SB, Okeke A, Stenson WF (2002) Phytosterols that are naturally present in commercial corn oil significantly reduce cholesterol absorption in humans. Am J Clin Nutr 75:1000–1004

    PubMed  CAS  Google Scholar 

  92. Pallottini V, Martini C, Cavallini G, Donati A, Bergamini E, Notarnicola M, Caruso MG, Trentalance A (2006) Modified HMG-CoA reductase and LDLr regulation is deeply involved in age-related hypercholesterolemia. J Cell Biochem 98:1044–1053

    PubMed  CAS  Google Scholar 

  93. Pasqualini JR (2005) Enzymes involved in the formation and transformation of steroid hormones in the fetal and placental compartments. J Steroid Biochem Mol Biol 97:401–415

    PubMed  CAS  Google Scholar 

  94. Peng Y, Schwarz EJ, Lazar MA, Genin A, Spinner NB, Taub R (1997) Cloning, human chromosomal assignment, and adipose and hepatic expression of the CL-6/INSIG1 gene. Genomics 43:278–284

    PubMed  CAS  Google Scholar 

  95. Podar K, Anderson KC (2006) Caveolin-1 as a potential new therapeutic target in multiple myeloma. Cancer Lett 233:10–15

    PubMed  CAS  Google Scholar 

  96. Ribaux PG, Iynedjian PB (2003) Analysis of the role of protein kinase B (cAKT) in insulin-dependent induction of glucokinase and sterol regulatory element-binding protein 1 (SREBP1) mRNAs in hepatocytes. Biochem J 376:697–705

    PubMed  CAS  Google Scholar 

  97. Rosenblum SB, Huynh T, Afonso A, Davis HR Jr, Yumibe N, Clader JW, Burnett DA (1998) Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): a designed, potent, orally active inhibitor of cholesterol absorption. J Med Chem 41:973–980

    PubMed  CAS  Google Scholar 

  98. Robinet P, Fradagrada A, Monier MN, Marchetti M, Cogny A, Moatti N, Paul JL, Vedie B, Lamaze C (2006) Dynamin is involved in endolysosomal cholesterol delivery to the endoplasmic reticulum: role in cholesterol homeostasis. Traffic 7:811–823

    PubMed  CAS  Google Scholar 

  99. Roth G, Kotzka J, Kremer L, Lehr S, Lohaus C, Meyer HE, Krone W, Muller-Wieland D (2000) MAP kinases Erk1/2 phosphorylate sterol regulatory element-binding protein (SREBP)-1a at serine 117 in vitro. J Biol Chem 275:33302–33307

    PubMed  CAS  Google Scholar 

  100. Sakai J, Rawson RB, Espenshade PJ, Cheng D, Seegmiller AC, Goldstein JL, Brown MS (1998) Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells. Mol Cell 2:505–514

    PubMed  CAS  Google Scholar 

  101. Sato R, Inoue J, Kawabe Y, Kodama T, Takano T, Maeda M (1996) Sterol-dependent transcriptional regulation of sterol regulatory element-binding protein-2. J Biol Chem 271:26461–26464

    PubMed  CAS  Google Scholar 

  102. Sheng Z, Otani H, Brown MS, Goldstein JL (1995) Independent regulation of sterol regulatory element-binding proteins 1 and 2 in hamster liver. Proc Natl Acad Sci USA 92:935–938

    PubMed  CAS  Google Scholar 

  103. Shimano H, Horton JD, Hammer RE, Shimomura I, Brown MS, Goldstein JL (1996) Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J Biol Chem 98:1575–1584

    CAS  Google Scholar 

  104. Shimano H, Horton JD, Shimomura I, Hammer RE, Brown MS, Goldstein JL (1997) Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. J Clin Invest 99:846–854

    PubMed  CAS  Google Scholar 

  105. Shimomura I, Shimano H, Horton JD, Goldstein JL, Brown MS (1997) Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells. J Clin Invest 99:838–845

    Article  PubMed  CAS  Google Scholar 

  106. Siperstein MD, Chaikoff IL, Reinhardt WO (1952) C14-Cholesterol. V. obligatory function of bile in intestinal absorption of cholesterol. J Biol Chem 198:111–114

    PubMed  CAS  Google Scholar 

  107. Steffensen KR, Gustafsson JA (2004) Putative metabolic effects of the liver X receptor (LXR). Diabetes 53(Suppl. 1):S36–S42

    PubMed  CAS  Google Scholar 

  108. Sudhop T, Lutjohann D, Kodal A, Igel M, Tribble DL, Shah S, Perevozskaya I, von Bergmann K (2002) Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation 106:1943–1948

    PubMed  CAS  Google Scholar 

  109. Sugii S, Reid PC, Ohgami N, Du H, Chang TY (2003) Distinct endosomal compartments in early trafficking of low density lipoprotein-derived cholesterol. J Biol Chem 278:27180–27189

    PubMed  CAS  Google Scholar 

  110. Sun LP, Li L, Goldstein JL, Brown MS (2005) Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro. J Biol Chem 280:26483–26490

    PubMed  CAS  Google Scholar 

  111. Sundqvist A, Ericsson J (2003) Transcription-dependent degradation controls the stability of the SREBP family of transcription factors. Proc Natl Acad Sci USA 100:13833–13838

    PubMed  CAS  Google Scholar 

  112. Tontonoz P, Mangelsdorf DJ (2003) Liver X receptor signaling pathways in cardiovascular disease. Mol Endocrinol 17:985–993

    PubMed  CAS  Google Scholar 

  113. Traber MG, Kayden HJ, Rindler MJ (1987) Polarized secretion of newly synthesized lipoproteins by the Caco-2 human intestinal cell line. J Lipid Res 28:1350–1363

    PubMed  CAS  Google Scholar 

  114. Tso P, Drake DS, Black DD, Sabesin SM (1984) Evidence for separate pathways of chylomicron and very low-density lipoprotein assembly and transport by rat small intestine. Am J Physiol 247:G599–G610

    PubMed  CAS  Google Scholar 

  115. Turley SD, Dietschy JM (2003) Sterol absorption by the small intestine. Curr Opin Lipidol 14:233–240

    PubMed  CAS  Google Scholar 

  116. Turley SD, Schwarz M, Spady DK, Dietschy JM (1998) Gender-related differences in bile acid and sterol metabolism in outbred CD-1 mice fed low- and high-cholesterol diets. Hepatology 28:1088–1094

    PubMed  CAS  Google Scholar 

  117. Uchida K, Nomura Y, Kadowaki M, Takase H, Takano K, Takeuchi N (1978) Age-related changes in cholesterol and bile acid metabolism in rats. J Lipid Res 19:544–552

    PubMed  CAS  Google Scholar 

  118. Vahouny GV, Connor WE, Roy T, Lin DS, Gallo LL (1981) Lymphatic absorption of shellfish sterols and their effects on cholesterol absorption. Am J Clin Nutr 34:507–513

    PubMed  CAS  Google Scholar 

  119. Vahouny GV, Roy T, Gallo LL, Story JA, Kritchevsky D, Cassidy M, Grund BM, Treadwell CR (1978) Dietary fiber and lymphatic absorption of cholesterol in the rat. Am J Clin Nutr 31(10 Suppl):S208–S210

    PubMed  CAS  Google Scholar 

  120. Valdivieso V, Palma R, Wunkhaus R, Antezana C, Severin C, Contreras A (1978) Effect of aging on biliary lipid composition and bile acid metabolism in normal Chilean women. Gastroenterology 74(5 Pt 1):871–874

    PubMed  CAS  Google Scholar 

  121. Vanhanen H, Kesaniemi YA, Miettinen TA (1992) Pravastatin lowers serum cholesterol, cholesterol-precursor sterols, fecal steroids, and cholesterol absorption in man. Metabolism 41:588–595

    PubMed  CAS  Google Scholar 

  122. Wang DQ, Carey MC (1996) Complete mapping of crystallization pathways during cholesterol precipitation from model bile: influence of physical-chemical variables of pathophysiologic relevance and identification of a stable liquid crystalline state in cold, dilute and hydrophilic bile salt-containing systems. J Lipid Res 37:606–630

    PubMed  CAS  Google Scholar 

  123. Wang D, Sul HS (1998) Insulin stimulation of the fatty acid synthase promoter is mediated by the phosphatidylinositol 3-kinase pathway. Involvement of protein kinase B/Akt. J Biol Chem 273:25420–25426

    PubMed  CAS  Google Scholar 

  124. Wang DQ (2002) Aging per se is an independent risk factor for cholesterol gallstone formation in gallstone susceptible mice. J Lipid Res 43:1950–1959

    PubMed  CAS  Google Scholar 

  125. Wang DQ (2003) New concepts of mechanisms of intestinal cholesterol absorption. Ann Hepatol 2:113–121

    PubMed  CAS  Google Scholar 

  126. Wang DQ, Lammert F, Cohen DE, Paigen B, Carey MC (1999) Cholic acid aids absorption, biliary secretion, and phase transitions of cholesterol in murine cholelithogenesis. Am J Physiol 276(3 Pt 1):G751–G760

    PubMed  CAS  Google Scholar 

  127. Wang DQ, Tazuma S, Cohen DE, Carey MC (2003) Feeding natural hydrophilic bile acids inhibits intestinal cholesterol absorption: studies in the gallstone-susceptible mouse. Am J Physiol Gastrointest Liver Physiol 285:G494–G502

    PubMed  CAS  Google Scholar 

  128. Wang HH, Afdhal NH, Wang DQ (2004) Estrogen receptor alpha, but not beta, plays a major role in 17-beta-estradiol-induced murine cholesterol gallstones. Gastroenterology 127:239–249

    PubMed  CAS  Google Scholar 

  129. Wang X, Sato R, Brown MS, Hua X, Goldstein JL (1994) SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. Cell 77:53–62

    PubMed  CAS  Google Scholar 

  130. Weber LW, Boll M, Stampfl A (2004) Maintaining cholesterol homeostasis: sterol regulatory element-binding proteins. World J Gastroenterol 10:3081–3087

    PubMed  CAS  Google Scholar 

  131. Yabe D, Brown MS, Goldstein JL (2002) Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. Proc Natl Acad Sci USA 99:12753–12758

    PubMed  CAS  Google Scholar 

  132. Yuan G, Wang J Hegele RA (2006) Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease. Can Med Assoc J 174:1124–1129

    Google Scholar 

  133. Zannis VI, Chroni A, Kypreos KE, Kan HY, Cesar TB, Zanni EE, Kardassis D (2004) Probing the pathways of chylomicron and HDL metabolism using adenovirus-mediated gene transfer. Curr Opin Lipidol 15:151–166

    PubMed  CAS  Google Scholar 

  134. Zelcer N, Tontonoz P (2006) Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest 116:607–614

    PubMed  CAS  Google Scholar 

  135. Zilversmit DB (1965) The composition and structure of lymph chylomicrons in dog, rat, and man. J Clin Invest 44:1610–1622

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors are gratefully indebted to Prof. Anna Trentalance (Full Professor of Physiology, University of “ROMA TRE”) for the helpful discussion.

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  1. Department of Biology, University of Rome “Roma Tre”, Viale Marconi, 446, 00146, Rome, Italy

    C. Martini & V. Pallottini

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Martini, C., Pallottini, V. Cholesterol: from feeding to gene regulation. Genes Nutr 2, 181–193 (2007). https://doi.org/10.1007/s12263-007-0049-y

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