Open AccessNuclear Transport Modulation Reduces Hypercholesterolemia, Atherosclerosis, and Fatty Liver
Author(s) -
Liu Yan,
Major Amy S.,
Zienkiewicz Jozef,
Gabriel Curtis L.,
Veach Ruth Ann,
Moore Daniel J.,
Collins Robert D.,
Hawiger Jacek
Publication year - 2013
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.113.000093
Subject(s) - hyperlipidemia , medicine , endocrinology , triglyceride , fatty liver , cholesterol , inflammation , transactivation , liver x receptor , nuclear receptor , transcription factor , biology , biochemistry , diabetes mellitus , disease , gene
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 W estern 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 SREBP s 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.