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

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