title: Bolstering cholesteryl ester hydrolysis in liver: A hepatocyte-targeting gene delivery strategy for potential alleviation of atherosclerosis.
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.
authors.affiliation: Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA, 23219, United States.
authors.forename: Hongliang
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, 23284, United States.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Lancina
authors.affiliation: Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, 23298, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory Sciences, Virginia Commonwealth University, Richmond, VA, 23298, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Korzun
authors.affiliation: Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA, 23219, United States; Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, 23298, United States; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, United States. Electronic address: hyang2@vcu.edu.
authors.forename: Hu
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, 23298, United States. Electronic address: shobha@vcu.edu.
authors.forename: Shobha
authors.initials: S
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000473:pathology / Q000628:therapy*; D001646:Bile / Q000378:metabolism; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000737:chemistry*; D050091:Dendrimers / Q000737:chemistry; D004705:Endocytosis; D005243:Feces / Q000737:chemistry; D005690:Galactose / Q000737:chemistry; D018014:Gene Transfer Techniques; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D042541:Intracellular Space / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D010957:Plasmids / Q000378:metabolism; D002787:Sterol Esterase / Q000378:metabolism
chemical_list: D002788:Cholesterol Esters; D050091:Dendrimers; C104700:PAMAM Starburst; D002787:Sterol Esterase; D005690:Galactose
keywords: Atherosclerosis; CEH; Galactose; Gene delivery; Hepatocyte targeting; PAMAM dendrimer