Sterol O‐Acyltransferase 2‐Driven Cholesterol Esterification Opposes Liver X Receptor‐Stimulated Fecal Neutral Sterol Loss

Abstract

Statin drugs have proven a successful and relatively safe therapy for the treatment of atherosclerotic cardiovascular disease (CVD). However, even with the substantial low-density lipoprotein (LDL) cholesterol lowering achieved with statin treatment, CVD remains the top cause of death in developed countries. Selective inhibitors of the cholesterol esterifying enzyme sterol-O acyltransferase 2 (SOAT2) hold great promise as effective CVD therapeutics. In mouse models, previous work has demonstrated that either antisense oligonucleotide (ASO) or small molecule inhibitors of SOAT2 can effectively reduce CVD progression, and even promote regression of established CVD. Although it is well known that SOAT2-driven cholesterol esterification can alter both the packaging and retention of atherogenic apoB-containing lipoproteins, here we set out to determine whether SOAT2-driven cholesterol esterification can also impact basal and liver X receptor (LXR)-stimulated fecal neutral sterol loss. These studies demonstrate that SOAT2 is a negative regulator of LXR-stimulated fecal neutral sterol loss in mice.

ACAT2 as a novel therapeutic target to treat fatty liver disease

“…Alternatively, the higher beta‐oxidation in muscle may be secondary to increased availability of energy substrate transported by lipoproteins. Finally, Soat2 is highly expressed in the intestine, and inactivation/downregulation of Soat2 in mice results in an increased fecal loss of neutral sterols [9, 10]. This aspect, not examined in the work by Pramfalk et al., may also have contributed to the beneficial effect against NAFLD.…”