Targeting Sterol O-Acyltransferase/Acyl-CoA:Cholesterol Acyltransferase (ACAT): A Perspective on Small-Molecule Inhibitors and Their Therapeutic Potential

Q1 · MEDICINE

Review

Author: Bhattacharjee, Pinaki ; Iyer, Malliga R. ; Rutland, Nicholas

Sterol O-acyltransferase (SOAT) is a membrane-bound enzyme that aids the esterification of cholesterol and fatty acids to cholesterol esters. SOAT has been studied extensively as a potential drug target, since its inhibition can serve as an alternative to statin therapy. Two SOAT isozymes that have discrete functions in the human body, namely, SOAT1 and SOAT2, have been characterized. Over three decades of research has focused on candidate SOAT1 inhibitors with unsatisfactory results in clinical trials. Recent research has focused on targeting SOAT2 selectively. In this perspective, we summarize the literature covering various SOAT inhibitory agents and discuss the design, structural requirements, and mode of action of SOAT inhibitors.

01 Sep 2022·Prostate Cancer and Prostatic DiseasesQ2 · MEDICINE

High expression of Sterol-O-Acyl transferase 1 (SOAT1), an enzyme involved in cholesterol metabolism, is associated with earlier biochemical recurrence in high risk prostate cancer

Q2 · MEDICINE

Article

Author: Fassnacht, Martin ; Eckhardt, Carolin ; Kübler, Hubert ; Spahn, Martin ; Sbiera, Iuliu ; Krebs, Markus ; Joniau, Steven ; Weigand, Isabel ; Sbiera, Silviu ; Kneitz, Burkhard ; Kroiss, Matthias

AbstractBackgroundProstate cancer (PCa) is the most frequent cancer in men. The prognosis of PCa is heterogeneous with many clinically indolent tumors and rare highly aggressive cases. Reliable tissue markers of prognosis are lacking. Active cholesteryl ester synthesis has been associated with prostate cancer aggressiveness. Sterol-O-Acyl transferases (SOAT) 1 and 2 catalyze cholesterol esterification in humans.ObjectiveTo investigate the value of SOAT1 and SOAT2 tissue expression as prognostic markers in high risk PCa.Patients and methodsFormalin-fixed paraffin-embedded tissue samples from 305 high risk PCa cases treated with radical prostatectomy were analyzed for SOAT1 and SOAT2 protein expression by semi-quantitative immunohistochemistry. The Kaplan–Meier method and Cox proportional hazards modeling were used to compare outcome.Main outcome measureBiochemical recurrence (BCR) free survival.ResultsSOAT1 expression was high in 73 (25%) and low in 219 (75%; not evaluable: 13) tumors. SOAT2 was highly expressed in 40 (14%) and at low levels in 249 (86%) samples (not evaluable: 16). By Kaplan–Meier analysis, we found significantly shorter median BCR free survival of 93 months (95% confidence interval 23.6–123.1) in patients with high SOAT1 vs. 134 months (112.6–220.2, Log-rank p < 0.001) with low SOAT1. SOAT2 expression was not significantly associated with BCR. After adjustment for age, preoperative PSA, tumor stage, Gleason score, resection status, lymph node involvement and year of surgery, high SOAT1 but not SOAT2 expression was associated with shorter BCR free survival with a hazard ratio of 2.40 (95% CI 1.57–3.68, p < 0.001). Time to clinical recurrence and overall survival were not significantly associated with SOAT1 and SOAT2 expressionConclusionsSOAT1 expression is strongly associated with BCR free survival alone and after multivariable adjustment in high risk PCa. SOAT1 may serve as a histologic marker of prognosis and holds promise as a future treatment target.

19 Mar 2021·Evidence-Based Complementary and Alternative MedicineQ4 · MEDICINE

Combined Lipidomics and Network Pharmacology Study of Protective Effects of Salvia miltiorrhiza against Blood Stasis Syndrome

Q4 · MEDICINE

ArticleOA

Author: Jin, Yidian ; Zhang, Hongyang ; Hu, Ping ; Xiao, Xue ; Xie, Zhiru ; Wang, Leqi ; Zeng, Xiangyu ; Li, Shasha

Blood stasis syndrome (BSS) is one of the most common symptoms of cardiovascular diseases (CVDs) in traditional Chinese medicine (TCM) theory. Previous studies have identified that Salvia miltiorrhiza (Danshen) has beneficial effects on BSS, but there is no relevant research from the perspective of lipidomics to study the mechanism of Danshen against BSS since hyperlipidemia has been the widely accepted risk factor of CVDs. In this study, lipidomics technology combined with network pharmacology was applied to investigate the pathological mechanism of BSS and the protective effects of Danshen. The lipidomics profiling based on the UPLC-QTOF-MS analysis method was applied to identify the differential metabolites in the plasma of blood stasis rats. The related pathway and potential targets involved in the anti-BSS effects of Danshen were predicted by pathway analysis and network pharmacology. The biochemical results showed that Danshen intervention significantly reduced whole blood viscosity (WBV) at all the shear rates and fibrinogen concentration (FIB)

(p < 0.01)

and increased activated partial thromboplastin time (APTT) effectively

(p < 0.01)

. We also found that 52 lipid metabolites, including glycerophospholipid, sphingolipid, glycerolipid, plasmalogen, cholesterol ester, and testosterone, were associated with blood stasis. Moreover, Dgka, Hsd17b3, Hsd3b1, Inppl1, Lpl, Pik3ca, Pik3r1, Pla2g1b, Pla2g2a, Soat1, and Soat2 were predicted as potential targets, while glycerophospholipid metabolism, glycerolipid metabolism, steroid and steroid hormone biosynthesis, phosphatidylinositol signaling system, and ether lipid metabolism were involved as shared critical pathways of lipidomics analysis and network pharmacology. Collectively, this study offered a new understanding of the protection mechanism of Danshen against BSS, which provided new insight to explore the protective effects of Danshen.

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