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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.
Prostate cancer proteomics: clinically useful protein biomarkers and future perspectives
Published in Expert Review of Proteomics, 2018
Paula Intasqui, Ricardo P. Bertolla, Marcus Vinicius Sadi
Proteomic studies have also been conducted to understand the mechanism of castration resistance in prostate cancer cell lines. Androgen-deprivation therapy is the treatment of choice for cases of cancer recurrence and metastatic disease, which, in turn, generally induces the disease to evolve to a castration-resistant phenotype [35]. In this case, cancer cells continue to respond to residual androgen levels, or even in complete absence of androgens, and this has been suggested to be related to androgen receptors amplification, overexpression, splicing variants and/or mutation [35]. Therefore, the proteomes of LNCaP and LNCaP androgen-independent derivative (LNCaP-SF) cells were compared, and 88 differentially expressed proteins were identified. Of these, hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2) presented with a ninefold increase in LNCaP-SF cells. Because this protein is involved in the ketogenic pathway, other proteins of this pathway were also observed to be increased in androgen-independent cells, that is, acetyl-CoA acetyltransferase, mitochondrial (ACAT1); D-beta-hydroxybutyrate dehydrogenase, mitochondrial (BDH1); hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL); and succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial (OXCT1). This was confirmed by western blotting and in prostate cancer tissues at mRNA and protein levels. ACAT1 was highly increased in metastatic prostate cancer tissues of men with the castration-resistant phenotype [36].
Downregulation of Acat1 by miR-21 may participate in liver fibrosis upon chronic DDT exposure
Published in Toxicology Mechanisms and Methods, 2020
Mikhail D. Chanyshev, Andrey A. Yarushkin, Elena V. Koldysheva, Elena L. Lushnikova, Lyudmila F. Gulyaeva
ACAT1 has been previously reported to play a key role in the regulation of cellular cholesterol levels, making this enzyme a target in the treatment of cardiovascular and neurodegenerative diseases (Chang et al. 2009). ACAT1 is also known to regulate fatty acid metabolism, and its expression was found to be decreased in obese patients with type 2 diabetes (Dharuri et al. 2014). In addition, a deficiency of ACAT1 enhanced liver fibrosis in a mouse model (Tomita et al. 2014). This phenomenon explains the hepatocyte lipid infiltration upon long-term DDT exposure. In conclusion, our, data indicate that the action of DDT is mediated through the interaction of miR-21 and Acat1 mRNA, which may be one of the molecular mechanisms of the pathogenesis of fibrosis.
Sericin-mediated improvement of dysmorphic cardiac mitochondria from hypercholesterolaemia is associated with maintaining mitochondrial dynamics, energy production, and mitochondrial structure
Published in Pharmaceutical Biology, 2022
Kitiya Rujimongkon, Sumate Ampawong, Duangnate Isarangkul, Onrapak Reamtong, Pornanong Aramwit
For the other three energy production pathways, including fatty acid oxidation (HSDL2, ACAT1, and ACADYL), the Krebs cycle (FH and ACO2), and the electron transport chain (SDHA, UQCRC2, NDUFA10, and ETFDH), the differentially expressed proteins were mixed in terms of upregulation and downregulation after sericin treatment in cardiac mitochondria under hypercholesterolemic conditions. Two proteins, ACAT1 and NDUFA10, were the most significantly upregulated proteins after sericin treatment. Immunofluorescence and immunogold labelling validation clearly revealed upregulated expression of ACAT1 and NDUFA10 in cardiac tissue and mitochondrial organelles, respectively. These data confirmed the correlation between protein expression and mitochondrial structure. In terms of function, ACAT1 is involved in the fatty acid oxidation pathway (Fukao et al. 1998). This enzyme plays a role in posttranslational modification-regulated mitochondrial protein activity (Still et al. 2013). In cardiovascular diseases, a lack of ACAT1 has been shown to increase the risk of atherosclerosis in a hypercholesterolaemia mouse model (Wakabayashi et al. 2018). Therefore, the increase in ACAT1 expression after sericin treatment may imply that the improved mitochondrial energy production is related to the fatty acid oxidation pathway and cardiovascular protection. Another protein, NDUFA10, functions in complex I of the electron transport chain and is involved in antioxidative stress. Silencing NDUFA10 results in a decreased number of mitochondria (Pandey et al. 2017). This finding supports our data, as upregulated NDUFA10 expression resulted in an increase in the number of normal-stage mitochondria. This result indicated that sericin upregulated NDUFA10 expression, leading to greater electron transport chain activity, increased antioxidative protection, and consequently recovered mitochondrial architecture.