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Lipoprotein Metabolism and Implications for Atherosclerosis Risk Determination and Treatment Decisions
Published in P. K. Shah, Risk Factors in Coronary Artery Disease, 2006
H. Robert Superko, Szilard Voros, Spencer King III
ACAT serves to convert free cholesterol to esterified cholesterol intracellularly through an esterification process. Approximately seven years ago, two different forms of ACAT were described: ACAT1 and ACAT2 (50). These two forms differ in regard to cellular location and potential impact on atherosclerosis (51), and ACAT1 appears to be expressed in most tissues in the body. In cholesterol-laden cells it serves to prevent intracellular free cholesterol–induced aptosis. This is particularly important for cell survival in macrophages located in atherosclerotic plaques. ACAT2 is located in small intestine enterocytes and hepatocytes. The role of ACAT2 appears to be to esterify cholesterol that is incorporated in VLDL particles, which eventually transform into LDL particles. It has been suggested that inhibition of ACAT2 may be a therapeutic approach to LDL-C reduction. Conversely, inhibition of ACAT1 may be detrimental due to possible disruption of plaque stability due to toxic macrophage death in existing atherosclerotic lesions. The ACAT inhibitor pactimibe, was recently reported not to have any beneficial effect on intravascular ultrasound–determined coronary atherosclerosis progression in humans (52). Future therapies that target ACAT2 may provide a novel means of reducing LDL-C.
Synthesis and biological evaluation of novel thienopyrimidine derivatives as diacylglycerol acyltransferase 1 (DGAT-1) inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Dong Jin Hong, Seung Hyun Jung, Jisook Kim, Danbee Jung, Young Gil Ahn, Kwee Hyun Suh, Kyung Hoon Min
Interestingly, the isomers 17a and 17b were more potent than mixture 14i, and even compound 2, in SF9 cells (Table 2). However, pharmacokinetic studies demonstrated that cis-isomer 17a had a much better profile than trans-isomer 17b (Table 3). 17a had a shorter half-life (1.2 h), but had much better bioavailability, compared to 17b. In enzymatic assays, 17a had an IC50 of 61 nM for DGAT-1 and displayed high off-target selectivity against DGAT-2, acyl-coenzyme A (CoA):cholesterol acyltransferases (ACAT1 and ACAT2) (Table 2). ACATs have sequence homology to DGAT-1 and play essential roles in cholesterol homeostasis23. 17b was not explored in the enzymatic assays due to its poor pharmacokinetic profile.
Gene expression profiling of rat livers after continuous whole-body exposure to low-dose rate of gamma rays
Published in International Journal of Radiation Biology, 2018
Acetyl-CoA is at the center of lipid metabolism. Cytosolic acetyl-CoA synthesis, which is essential for de novo lipogenesis, was reduced in response to the low-dose-rate radiation. The cytosolic pool of acetyl-CoA is mainly supplied by two different ATP-dependent reactions: cleavage of citrate, which is generated from TCA cycle, into oxaloacetate and acetyl-CoA by ATP citrate lyase (ACLY) or the ligation of acetate and CoA by acetyl-CoA synthetase (ACSS) (Schug et al. 2015). Both ACLY and ACSS2, the cytosolic ACSS, were transcriptionally down-regulated in this study. Another pathway in producing cytosolic acetyl-CoA was through converting acetoacetate to acetoacetyl-CoA by acetoacetyl-CoA synthetase (AACS) and subsequently to acetyl-CoA by acetyl-CoA acetyltransferase 2 (ACAT2). This acetyl-CoA synthesis was also decreased as both Aacs and Acat2 genes were down-regulated.
Administration timing and duration-dependent effects of sesamin isomers on lipid metabolism in rats
Published in Chronobiology International, 2020
Norifumi Tateishi, Satoshi Morita, Izumi Yamazaki, Hitoshi Okumura, Masaru Kominami, Sota Akazawa, Ayuta Funaki, Namino Tomimori, Tomohiro Rogi, Hiroshi Shibata, Shigenobu Shibata
Although some of the conditions differed from those we used, various studies have been performed on rats, hamsters, and other animals to examine cholesterol metabolism with SE. In those studies, the enzyme activity inhibition of HMGCR, involved in cholesterol synthesis, and suppression of gene expression were proposed as mechanisms for reducing cholesterol by SE (Hirose et al. 1991; Ide et al. 2009; Liang et al. 2015). In contrast, no effects were seen on the expression of the Ldlr gene, which is involved in low-density lipoprotein particle uptake (Liang et al. 2015; Rogi et al. 2011). These notions are partially consistent with our finding that both gene expression of Hmgcr and Ldlr was suppressed. We also confirmed that SE significantly suppressed gene expression of acetyl-CoA acetyltransferase 2 (Acat2), which converts cholesterol into cholesterol ester (data not shown), and this is also consistent with a previous report (Liang et al. 2015). These data indicate that SE affects the expression of these genes, thus reducing cholesterol. Meanwhile, SE has been shown to promote expression of the Cyp7a1 gene, a catabolic enzyme that converts cholesterol into bile acid, in a previous study (Liang et al. 2015), but we did not observe any effects of SE on Cyp7a1 gene expression in our tests. Another study found that gene expression of Abcg5 and Abcg8, which are involved in the excretion of cholesterol from the liver, is not affected by SE (Rogi et al. 2011), but our results showed that SE promoted their expression, which might partly contribute to the decrease in cholesterol that we observed.