Acute sterol o-acyltransferase 2 (SOAT2) knockdown rapidly mobilizes hepatic cholesterol for fecal excretion.

Stephanie M Marshall,Martha D Wilson,Matthew A Davis,Rosanne M Crooke,Anthony D Gromovsky,Kathryn L Kelley,Lawrence L Rudel,J Mark Brown,Richard G Lee,Mark J Graham,Ryan E Temel

doi:10.1371/journal.pone.0098953

Abstract

The primary risk factor for atherosclerotic cardiovascular disease is LDL cholesterol, which can be reduced by increasing cholesterol excretion from the body. Fecal cholesterol excretion can be driven by a hepatobiliary as well as a non-biliary pathway known as transintestinal cholesterol efflux (TICE). We previously showed that chronic knockdown of the hepatic cholesterol esterifying enzyme sterol O-acyltransferase 2 (SOAT2) increased fecal cholesterol loss via TICE. To elucidate the initial events that stimulate TICE, C57Bl/6 mice were fed a high cholesterol diet to induce hepatic cholesterol accumulation and were then treated for 1 or 2 weeks with an antisense oligonucleotide targeting SOAT2. Within 2 weeks of hepatic SOAT2 knockdown (SOAT2HKD), the concentration of cholesteryl ester in the liver was reduced by 70% without a reciprocal increase in hepatic free cholesterol. The rapid mobilization of hepatic cholesterol stores resulted in a ∼2-fold increase in fecal neutral sterol loss but no change in biliary cholesterol concentration. Acute SOAT2HKD increased plasma cholesterol carried primarily in lipoproteins enriched in apoB and apoE. Collectively, our data suggest that acutely reducing SOAT2 causes hepatic cholesterol to be swiftly mobilized and packaged onto nascent lipoproteins that feed cholesterol into the TICE pathway for fecal excretion.

Highlights

Despite advances in treatment and prevention, cardiovascular disease remains the number one killer of Americans [1]
Chronic hepatic knockdown of sterol O-acyl transferase 2 (SOAT2) expression appears to stimulate transintestinal cholesterol efflux (TICE) resulting in increased cholesterol excretion and decreased LDL cholesterol (LDLc) concentration [21]
In mice that had been previously fed a high-cholesterol diet to induce hepatic cholesteryl esters (CE) accumulation, treatment with SOAT2 ASO for 1-2 weeks caused 1) knockdown of hepatic SOAT2 expression and rapid depletion of CE from the liver, 2) increased plasma free cholesterol (FC) carried on apoB- and apoE-containing lipoproteins and 3) elevated fecal neutral sterol excretion without major perturbations in biliary cholesterol

Summary

Introduction

Despite advances in treatment and prevention, cardiovascular disease remains the number one killer of Americans [1]. High blood concentrations of LDL cholesterol (LDLc) lead to the development of atherosclerosis, which is the principal cause of the majority of clinical cardiovascular events [1]. By inhibiting cholesterol synthesis and increasing LDL clearance from the blood, statins have the ability to significantly reduce LDLc and have been shown to reduce the risk of cardiovascular disease by as much as 44% [2]. Deficiency of Soat in liver results in the secretion of VLDL that are depleted of CE [12] resulting in a significant reduction in plasma VLDLc concentration [10,13,14,15,16]. Regardless of plasma LDLc concentration, Soat deficiency significantly reduces atherosclerosis development in Ldlr-/- and Apoe-/- mice [13,14,15,17]. The reduced atherogenicity of LDL from Soat deficient mice appears to be caused in part by SOAT2-derived cholesteryl oleate depletion that decreases LDL binding to proteoglycans [13]

Methods

Results

Conclusion