Acyl-Coenzyme A: Cholesterol Acyltransferase (ACAT) in Cholesterol Metabolism: From Its Discovery to Clinical Trials and the Genomics Era

Abstract

The purification and cloning of the acyl-coenzyme A: cholesterol acyltransferase (ACAT) enzymes and the sterol O-acyltransferase (SOAT) genes has opened new areas of interest in cholesterol metabolism given their profound effects on foam cell biology and intestinal lipid absorption. The generation of mouse models deficient in Soat1 or Soat2 confirmed the importance of their gene products on cholesterol esterification and lipoprotein physiology. Although these studies supported clinical trials which used non-selective ACAT inhibitors, these trials did not report benefits, and one showed an increased risk. Early genetic studies have implicated common variants in both genes with human traits, including lipoprotein levels, coronary artery disease, and Alzheimer’s disease; however, modern genome-wide association studies have not replicated these associations. In contrast, the common SOAT1 variants are most reproducibly associated with testosterone levels.

AUP1 regulates lipid metabolism and induces lipid accumulation to accelerate the progression of renal clear cell carcinoma

“…The downstream mechanism by which AUP1 regulates lipid metabolism was studied through multiple integration RNA‐seq analysis of differentially expressed genes involved in lipid storage, CHOL efflux, and CHOL storage (from GSEA). The results presented SOAT1 in the convergence diagram (Figure 5A), which catalyzes the formation of FA‐CE 22 . Further qPCR verification of ACHN and A498 cells after transfection showed that SOAT1 expression decreased significantly with AUP1 knockdown (Figure 5B).…”

“…The results presented SOAT1 in the convergence diagram (Figure 5A ), which catalyzes the formation of FA‐CE. 22 Further qPCR verification of ACHN and A498 cells after transfection showed that SOAT1 expression decreased significantly with AUP1 knockdown (Figure 5B ). The Clinical Proteomic Tumor Analysis Consortium database showed increased SOAT1 expression in ccRCC tissues, which gradually increased with the progression of tumor grade (Figure 5C ).…”

“…SOAT1, also known as acetyl‐CoA acetyltransferase 1 (ACAT1), belongs to the acyltransferase family and is located in the ER. 22 SOAT1 mainly catalyzes the formation of CE from intracellular free CHOL and stores them in LDs. 44 It can also provide acyl units for acetyl‐CoA at the initial stage of palmitic acid biosynthesis.…”

“…The latter can activate MAPK, PI3K/AKT, and NF-κB to enhance MMP2 and MMP9 expression, thereby promoting EMT 42,43. SOAT1, also known as acetyl-CoA acetyltransferase 1 (ACAT1), belongs to the acyltransferase family and is located in the ER 22. SOAT1 mainly catalyzes the formation of CE from intracellular free CHOL and stores them in LDs 44.…”

Evaluation of Subclinical Vascular Disease in Diabetic Kidney Disease: A Tool for Personalization of Management of a High-Risk Population

“…The pathogenesis of atherosclerosis in patients with DKD is multifactorial, with both conventional and emerging risk factors playing a role [ 7 ]. Recently, sterol-O-acyltransferase-1, an enzyme that esterifies free cholesterol, the NLRP3 inflammasome pathway and the interleukin-33/ST2 pathway have also been implicated in the atherogenetic process in these patients [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. Several previous reports observed greater atherosclerotic burden in the carotid arteries of patients with DKD than in diabetic patients with preserved renal function [ 32 , 33 , 34 , 35 ].…”