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  • In human neuroblastoma SH SY Y cells and

    2019-12-03

    In human neuroblastoma SH-SY5Y Polyphyllin VII and in lymphoma Jurkat cells, Yamanaka et al. [56] showed that exogenously added 24(S)-hydroxycholesterol could be efficiently esterified by ACAT1. These results suggest that both ACAT1 and ACAT2 can control the oxysterol levels by directly esterifying them, in a cell-type specific manner. ACAT could also control oxysterol levels by altering the cholesterol pool from which oxysterols are derived. For example, in the triple transgenic mouse model for Alzheimer’s disease, Bryleva et al. [3] reported that genetic ablation of ACAT1 increased the steady state concentration of 24(S)-hydroxycholesterol in the mouse brain. Bryleva et al. speculated that in the absence of cholesterol esterification, an increased substrate pool of cholesterol for biosynthesis of 24(S)-hydroxycholesterol might occur. In various cell types, sterol/steroid received from lipoproteins, and from endogenous biosynthesis can move to mitochondria where they can be metabolized to produce both oxysterols (OXY), such as 22(R)-hydroxycholesterol and 27-hydroxycholesterol, and steroids including PREG (PREG). The free cholesterol can also move to the ER to produce other cholesterol metabolites like 24(S)-hydroxycholesterol and 25-hydroxycholesterol by resident microsomal enzymes at the ER. These free sterol/steroid pool can be put in a storage form through the enzymatic action of acyl-CoA:cholesterol acyltransferase (ACAT1/SOAT1). ACAT1 has been reported to be enriched in the mitochondria associated membrane (MAM) [57], [58], which forms the transitional zones between the endoplasmic reticulum and the mitochondria. Thus, ACAT1 is in a position to esterify cholesterol and various cholesterol metabolites (i.e., oxysterols, PREG etc.) traversing through the mitochondria and ER membranes. The exact location of ACAT2 in various cell types is yet to be clarified.
    Future perspectives ACATs are drug targets. Previously, most of the effort has been focused on targeting ACAT to treat atherosclerosis. Recent work demonstrated substantial benefits of inhibiting ACAT1 in mouse models of Alzheimer’s disease [2], [3], [4], [5]. An additional area of interest is the role ACAT in cancer: ACAT inhibition has been used to block carcinogenesis in vitro in a variety of cancer types including breast cancer [59], glioblastoma [60], and lymphocytic leukemia [61]. In addition, ACAT1 has been suggested as a potential prognostic marker of prostate cancer progression [62]. Yue et al. [6] reported that advanced human prostate cancer samples had altered cholesteryl ester accumulation, and that blocking ACAT1 mediated cholesteryl ester storage reduced cancer proliferation, impaired its invasive capabilities, and suppressed tumor growth in a mouse model. The authors proposed that the mechanism of action was to work through increased free cholesterol following ACAT1 inhibition, leading to inhibition of sterol regulatory element-binging protein (SREBP) mediated transcription of the low-density lipoprotein receptor (LDLR). The mechanism as proposed is plausible. In addition, given the connection between ACAT and oxysterol esterification, and the role of oxysterols in regulation of cell growth in liver cancer cells [55], it would be worthwhile to explore whether ACAT inhibition alters oxysterol levels in prostate or other cancer models. The existing ACAT inhibitors have both positive and negative attributes, as reviewed in Chang et al. [1] and in Ohshiro and Tomoda [63]. The identification of PREG as an ACAT substrate but not as an activator may help to identify novel ACAT inhibitors that inhibit the allosteric property of ACAT1 without interfering the enzyme\'s active sites. Such inhibitors would provide more specificity and with less toxicity than the traditional active site inhibitors. PREG is the precursor for all neurosteroids. The fact that ACAT1 uses PREG as an excellent substrate suggests that ACAT1 may play a key role in controlling the free PREG content in the central nervous system. These are some of the open areas of investigations in the future.