Ruth Veach
Last active: 4/25/2016

Nuclear transport modulation reduces hypercholesterolemia, atherosclerosis, and fatty liver.

Liu Y, Major AS, Zienkiewicz J, Gabriel CL, Veach RA, Moore DJ, Collins RD, Hawiger J
J Am Heart Assoc. 2013 2 (2): e000093

PMID: 23563994 · PMCID: PMC3647260 · DOI:10.1161/JAHA.113.000093

BACKGROUND - Elevated cholesterol and triglycerides in blood lead to atherosclerosis and fatty liver, contributing to rising cardiovascular and hepatobiliary morbidity and mortality worldwide.

METHODS AND 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.

MeSH Terms (19)

Active Transport, Cell Nucleus Animals Atherosclerosis Cell-Penetrating Peptides Cell Nucleus Cholesterol Dietary Fats Disease Models, Animal Fatty Liver Female Hypercholesterolemia Liver Mice Mice, Transgenic NF-kappa B Peptides Sterol Regulatory Element Binding Proteins Transcription Factors Triglycerides

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