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 a central role of hepatic cholesteryl ester hydrolase (CEH) in intrahepatic hydrolysis of CE and subsequent removal of the resulting free cholesterol, in this work, we applied galactose-functionalized polyamidoamine (PAMAM) dendrimer G5 (Gal-G5) for hepatocyte-specific delivery of CEH expression vector. The data presented herein show increased specific uptake of Gal-G5 by the hepatocytes in vitro and in vivo. Furthermore, the upregulated CEH expression in the hepatocytes significantly enhanced intracellular hydrolysis of HDL-CE and subsequent conversion/secretion of hydrolyzed free cholesterol (FC) as bile acids. Increased CEH expression in the liver significantly increased the flux of HDL-CE to biliary as well as fecal FC and bile acids. Meanwhile, Gal-G5 did not induce hepatic or renal toxicity. It was 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 alleviation of atherosclerosis.

Development of mannose functionalized dendrimeric nanoparticles for targeted delivery to macrophages: use of this platform to modulate atherosclerosis

“…13,14 Intracellular CE accumulation in macrophages can be reduced by enhancing the removal of unesterified or free cholesterol (FC), a process rate-limited by intracellular CE hydro-lysis catalyzed by neutral CE hydrolase (CEH), 15,16 and earlier studies from our laboratory have demonstrated CEH overexpression-mediated increase in CE mobilization. 17–19 FC generated by CEH-mediated hydrolysis of CE becomes available for ApoA1 or High density lipoprotein-dependent efflux through FC transporters ABCA1/G1 20 and carried to the liver for final elimination from the body. Although overexpression of ABCA1 attenuates atherosclerosis, 21,22 deficiency of ABCA1 in macrophages enhances plaque progression.…”

Construction of dual nanomedicines for the imaging and alleviation of atherosclerosis

“…To improve the colloid stability in physiological conditions, the lifetime in blood circulation should be increased, and toxicity in vivo should be reduced; magnetite NPs are often coated or modified with biocompatible polymer molecules such as dextran and polyvinyl alcohol [9,11,12]. In this study, we used PEG-PEI to modify SPIO NPs, as it provides good solubility in aqueous solvents and prolongs circulation time in the bloodstream [20,32]. The TEM image indicated that profilin-1-labeled NPs displayed mono-dispersion, uniform size (average size ¼ 15-20 nm in the dry state) and spherical morphology (Figure 2(a)).…”

“…Currently, several clinic drugs are available that slow the progression of atherosclerosis by lowering plasma lipid levels [19,20]. However, the equally important contribution of inflammation to the development of cardiovascular disease is overlooked by current therapies [21].…”

Lipidomics in translational research and the clinical significance of lipid-based biomarkers

“…Cholesterol plays an important role in cell membrane fluidity by being able to both cause membrane stability and by decreasing flexibility of nearby unsaturated acyl chains in membranes. Cholesterol also helps to maintain fluidity through inhibition of acyl-chain packing of cellular membranes (92). …”

“…This pre-clinical work by Hongliang He and coworkers demonstrated a promising treatment for alleviating the accumulation of cholesterol esters in patients suffering from atherosclerosis. (92)…”