Abstract
The defect of low density lipoprotein receptor disturbs cholesterol metabolism and causes familial hypercholesterolaemia (FH). In this study, we directly delivered exogenous Ldlr gene into the liver of FH model mice (Ldlr −/−) by lentiviral gene transfer system. The results showed that the Ldlr gene controlled by hepatocyte-specific human thyroxine-binding globulin (TBG) promoter successfully and exclusively expressed in livers. We found that, although, the content of high density lipoprotein in serum was not significantly affected by the Ldlr gene expression, the serum low density lipoprotein level was reduced by 46%, associated with a 30% and 28% decrease in triglyceride and total cholesterol, respectively, compared to uninjected Ldlr −/− mice. Moreover, the TBG directed expression of Ldlr significantly decreased the lipid accumulation in liver and reduced plaque burden in aorta (32%). Our results indicated that the hepatocyte-specific expression of Ldlr gene strikingly lowered serum lipid levels and resulted in amelioration of hypercholesterolaemia.
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Anedda S., Mura S., Marcello C. and Pintus P. 2011 HELP LDL-apheresis in two cases of familial hypercholesterolemic pregnant women. Transfus. Apher. Sci. 44, 21–24.
Bish L. T., Sleeper M. M., Forbes S. C., Morine K. J., Reynolds C., Singletary G. E. et al. 2011 Long-term systemic myostatin inhibition via liver-targeted gene transfer in golden retriever muscular dystrophy. Hum. Gene Ther. 22, 1499–1509.
Carrillo-Carrasco N., Chandler R. J., Chandrasekaran S. and Venditti C. P. 2010 Liver-directed recombinant adeno-associated viral gene delivery rescues a lethal mouse model of methylmalonic acidemia and provides long-term phenotypic correction. Hum. Gene Ther. 21, 1147–1154.
Cotugno G., Annunziata P., Tessitore A., O’Malley T., Capalbo A., Faella A. et al. 2011 Long-term amelioration of feline mucopolysaccharidosis VI after AAV-mediated liver gene transfer. Mol. Ther. 19, 461–469.
Elis A., Zhou R. and Stein E. A. 2011 Effect of lipid-lowering treatment on natural history of heterozygous familial hypercholesterolemia in past three decades. Am. J. Cardiol. 108, 223–226.
Jacobs F., Wisse E. and De Geest B. 2010 The role of liver sinusoidal cells in hepatocyte-directed gene transfer. Am. J. Pathol. 176, 14–21.
Kaeppel C., Beattie S. G., Fronza R., van Logtenstein R., Salmon F., Schmidt S. et al. 2013 A largely random AAV integration profile after LPLD gene therapy. Nat. Med. 19, 889–891.
Kassim S. H., Li H., Vandenberghe L. H., Hinderer C., Bell P., Marchadier D. et al. 2010 Gene therapy in a humanized mousemodel of familial hypercholesterolemia leads to marked regression of atherosclerosis. PLoS One 5, e13424.
Küçükkartallar T., Yankol Y., Kanmaz T., Topaloğlu S., Acarli K. and Kalayoglu M. 2011 Liver transplantation as a treatment option for three siblings with homozygous familial hypercholesterolemia. Pediatr. Transplant. 15, 281–284.
Lugenbiel P., Bauer A., Kelemen K., Schweizer P. A., Becker R., Katus H. A. and Thomas D. 2012 Biological heart rate reduction through genetic suppression of G α(s) protein in the sinoatrial node. J. Am. Heart Assoc. 1, jah3-e000372.
Marais A. D. and Blom D. J. 2013 Recent advances in the treatment of homozygous familial hypercholesterolaemia. Curr. Opin. Lipidol. 24, 288–294.
Miltiadous G., Xenophontos S., Bairaktari E., Ganotakis M., Cariolou M. and Elisaf M. 2005 Genetic and environmental factors affecting the response to statin therapy in patients with molecularly defined familial hypercholesterolaemia. Pharmacogenet. Genomics 15, 219–225.
Nair D. R., Sharifi M. and Al-Rasadi K. 2014 Familial hypercholesterolaemia. Curr. Opin. Cardiol. 29, 381–388.
Orsoni A., Saheb S., Levels J. H., Dallinga-Thie G., Atassi M., Bittar R. et al. 2011 LDL-apheresis depletes apoE-HDL and pre- β1-HDL in familial hypercholesterolemia: relevance to atheroprotection. J. Lipid Res. 52, 2304–2313.
Ranzani M., Cesana D., Bartholomae C. C., Sanvito F., Pala M., Benedicenti F. et al. 2013 Lentiviral vector-based insertional mutagenesis identifies genes associated with liver cancer. Nat. Methods 10, 155–161.
Snoeys J., Lievens J., Wisse E., Jacobs F., Duimel H., Collen D. et al. 2007 Species differences in transgene DNA uptake in hepatocytes after adenoviral transfer correlate with the size of endothelial fenestrae. Gene Ther. 14, 604–612.
Tal J. 2000 Adeno-associated virus-based vectors in gene therapy. J. Biomed. Sci. 7, 279–291.
Uchida D., Shiraha H., Kato H., Nagahara T., Iwamuro M., Kataoka J. et al. 2014 Potential of adenovirus-mediated REIC/Dkk-3 gene therapy for use in the treatment of pancreatic cancer . J. Gastroenterol. Hepatol. 29, 973–983.
Van Craeyveld E., Gordts S. C., Nefyodova E., Jacobs F. and De Geest B. 2011 Regression and stabilization of advanced murine atherosclerotic lesions: a comparison of LDL lowering and HDL raising gene transfer strategies. J. Mol. Med. 89, 555–567.
Westphal M., Ylä-Herttuala S., Martin J., Warnke P., Menei P., Eckland D. et al. 2013 Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): a randomised, open-label, phase 3 trial. Lancet Oncol. 14, 823–833.
Wisse E., Jacobs F., Topal B., Frederik P. and De Geest B. 2008 The size of endothelial fenestrae in human liver sinusoids: implications for hepatocyte-directed gene transfer. Gene Ther. 15, 1193–1199.
Yan Z. H., Yan H. and Ou H. L. 2012 Human thyroxine binding globulin (TBG) promoter directs efficient and sustaining transgene expression in liver-specific pattern. Gene 506, 289–294.
Zeng H., He X., Hou X., Li L. and Chen J. X. 2014 Apelin gene therapy increases myocardial vascular density and ameliorates diabetic cardiomyopathy via upregulation of sirtuin 3. Am. J. Physiol. Heart Circ. Physiol. 306, 585–597.
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This study was supported by Guizhou Science and Technology Funds (no. 2012GZ81781) and the National Natural Science Foundation of China (no. 81460277).
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[Ou H., Zhang Q. and Zeng J. 2016 Improving lipoprotein profiles by liver-directed gene transfer of low density lipoprotein receptor gene in hypercholesterolaemia mice. J. Genet. 95, xx–xx]
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OU, H., ZHANG, Q. & ZENG, J. Improving lipoprotein profiles by liver-directed gene transfer of low density lipoprotein receptor gene in hypercholesterolaemia mice. J Genet 95, 311–316 (2016). https://doi.org/10.1007/s12041-016-0636-z
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DOI: https://doi.org/10.1007/s12041-016-0636-z