Faculty Collaboration Database

Bolstering cholesteryl ester hydrolysis in liver: A hepatocyte-targeting gene delivery strategy for potential alleviation of atherosclerosis. Biomaterials 2017 Jun;130:1-13

Date

03/30/2017

Pubmed ID

28349866

Pubmed Central ID

PMC5560268

DOI

10.1016/j.biomaterials.2017.03.024

Scopus ID

2-s2.0-85016083493 (requires institutional sign-in at Scopus site)   31 Citations

Abstract

Current atherosclerosis treatment strategies primarily focus on limiting further cholesteryl esters (CE) accumulation by reducing endogenous synthesis of cholesterol in the liver. No therapy is currently available to enhance the removal of CE, a crucial step to reduce the burden of the existing disease. Given the central role of hepatic cholesteryl ester hydrolase (CEH) in the intrahepatic hydrolysis of CE and subsequent removal of the resulting free cholesterol (FC), in this work, we applied galactose-functionalized polyamidoamine (PAMAM) dendrimer generation 5 (Gal-G5) for hepatocyte-specific delivery of CEH expression vector. The data presented herein show the increased specific uptake of Gal-G5/CEH expression vector complexes (simply Gal-G5/CEH) by hepatocytes in vitro and in vivo. Furthermore, the upregulated CEH expression in the hepatocytes significantly enhanced the intracellular hydrolysis of high density lipoprotein-associated CE (HDL-CE) and subsequent conversion/secretion of hydrolyzed FC as bile acids (BA). The increased CEH expression in the liver significantly increased the flux of HDL-CE to biliary as well as fecal FC and BA. Meanwhile, Gal-G5 did not induce hepatic or renal toxicity. It was also not immunotoxic. Because of these encouraging pre-clinical testing results, using this safe and highly efficient hepatocyte-specific gene delivery platform to enhance the hepatic processes involved in cholesterol elimination is a promising strategy for the alleviation of atherosclerosis.

Author List

He H, Lancina MG 3rd, Wang J, Korzun WJ, Yang H, Ghosh S

Author

Hu Yang PhD Chair, Professor in the Biomedical Engineering department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Atherosclerosis
Bile
Cells, Cultured
Cholesterol Esters
Dendrimers
Endocytosis
Feces
Galactose
Gene Transfer Techniques
Hepatocytes
Humans
Hydrolysis
Intracellular Space
Liver
Mice, Inbred C57BL
Organ Specificity
Plasmids
Sterol Esterase