title: Nuclear transport modulation reduces hypercholesterolemia, atherosclerosis, and fatty liver.
abstract: BACKGROUND
  Elevated cholesterol and triglycerides in blood lead to atherosclerosis and fatty liver, contributing to rising cardiovascular and hepatobiliary morbidity and mortality worldwide.
  
  
  RESULTS
  A cell-penetrating nuclear transport modifier (NTM) reduced hyperlipidemia, atherosclerosis, and fatty liver in low-density lipoprotein receptor-deficient mice fed a Western diet. NTM treatment led to lower cholesterol and triglyceride levels in blood compared with control animals (36% and 53%, respectively; P<0.005) and liver (41% and 34%, respectively; P<0.05) after 8 weeks. Atherosclerosis was reduced by 63% (P<0.0005), and liver function improved compared with saline-treated controls. In addition, fasting blood glucose levels were reduced from 209 to 138 mg/dL (P<0.005), and body weight gain was ameliorated (P<0.005) in NTM-treated mice, although food intake remained the same as that in control animals. The NTM used in this study, cSN50.1 peptide, is known to modulate nuclear transport of stress-responsive transcription factors such as nuclear factor kappa B, the master regulator of inflammation. This NTM has now been demonstrated to also modulate nuclear transport of sterol regulatory element-binding protein (SREBP) transcription factors, the master regulators of cholesterol, triglyceride, and fatty acid synthesis. NTM-modulated translocation of SREBPs to the nucleus was associated with attenuated transactivation of their cognate genes that contribute to hyperlipidemia.
  
  
  CONCLUSIONS
  Two-pronged control of inflammation and dyslipidemia by modulating nuclear transport of their critical regulators offers a new approach to comprehensive amelioration of hyperlipidemia, atherosclerosis, fatty liver, and their potential complications.
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School ofMedicine, Nashville, TN 37232, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Amy S
authors.initials: AS
authors.lastname: Major
authors.forename: Jozef
authors.initials: J
authors.lastname: Zienkiewicz
authors.forename: Curtis L
authors.initials: CL
authors.lastname: Gabriel
authors.forename: Ruth Ann
authors.initials: RA
authors.lastname: Veach
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Moore
authors.forename: Robert D
authors.initials: RD
authors.lastname: Collins
authors.forename: Jacek
authors.initials: J
authors.lastname: Hawiger
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D057846:Cell-Penetrating Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D002784:Cholesterol / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D051779:Sterol Regulatory Element Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D057846:Cell-Penetrating Peptides; D004041:Dietary Fats; D016328:NF-kappa B; D010455:Peptides; C118258:SN50 peptide; D051779:Sterol Regulatory Element Binding Proteins; D014157:Transcription Factors; D014280:Triglycerides; C583494:cSN50.1 peptide; D002784:Cholesterol
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