|CDCB156054||Rat ACAT1 ORF clone (NM_017075.2)||Inquiry|
|CDCB165559||Chicken ACAT1 ORF Clone (NM_001277779)||Inquiry|
|CDCB168446||Danio rerio ACAT1 ORF Clone (NM_001003746)||Inquiry|
|CDCB187406||Rabbit ACAT1 ORF clone (XM_002708492.2)||Inquiry|
|CDCR023564||Mouse Acat1 ORF clone (NM_144784.3)||Inquiry|
|CDCS405357||Human ACAT1 ORF Clone (BC010942)||Inquiry|
|MiUTR1M-01103||ACAT1 miRNA 3'UTR clone||Inquiry|
Acetyl-CoA acetyltransferase 1(ACAT1) is an endoplasmic reticulum membrane protein. Its N-terminus is located in the cytoplasm and the C-terminus is located in the endoplasmic reticulum lumen. Each transmembrane region contains a tyrosine protein kinase domain and two N-linked glycosylation sites with a leucine zinc finger motif at the N-terminus. ACAT1 is widely expressed in tissues, and the synthesized cholesterol ester (CE) is stored in lipid droplets.
In macrophages, ACAT1 regulates the ratio of cholesterol/CE. In macrophages, free cholesterol (FC) is partially esterified into CE by ACAT1 and stored in cells; part of it is effluxed out of cells, assembled into HDL, and involved in reverse cholesterol transport. Because of the blood-brain barrier, peripheral cholesterol cannot enter the brain, and cholesterol in the brain is synthesized by astrocytes. An excess of FC is esterified to CE under the action of ACAT1, and the other is a synthesis of 24-hydroxycholesterol under the action of cholesterol 24-hydroxylase (CYP46). 24-hydroxycholesterol can be transported back to the liver by LDL through the blood-brain barrier for metabolism. ACAT is a drug target for a variety of disease treatment interventions, including atherosclerosis, Alzheimer's disease, and cancer.
ACAT1 and Tumor
A number of in vitro studies have demonstrated that ACAT inhibitors can improve breast cancer, glioblastoma, and lymphocytic leukemia. In addition, ACAT1 is considered a prognostic indicator of prostate cancer progression. The cholesterol metabolism of activated CD8+ T cells is reprogrammed and more free cholesterol is synthesized to help the cells proliferate rapidly. This suggests that inhibition of ACAT1 activity up-regulates the level of cholesterol in the plasma membrane of CD8+ T cells, thereby enhancing T cell receptor clustering signals and forming more immune synapses. In turn, the production of cytokines and cytotoxic granzymes, the killing of tumors, and the proliferation of CD8+ T cells were significantly increased. Small molecule drugs that inhibit ACAT1 have been reported to have a therapeutic effect on cardiovascular disease and neurodegenerative diseases. Studies have shown that inhibition of ACAT1 has a clear effect on tumor immunotherapy and can be used as an adjunct to immunological test sites. It is also used in combination with anti-PD-1 antibodies to enhance the efficacy of immunotherapy from the perspective of cholesterol metabolism.
The Warburg effect, named after the 1931 Nobel laureate Otto Warburg, suggests that cancer cells tend to be inefficiently used by glucose, known as glycolysis, and dilute their mitochondria. Cancer cells benefit from this metabolic distortion, as by-products of glycolysis can serve as a building block for rapid growth. ACAT1 is a control valve that regulates the Warburg effect. Fan et al. found that the activity of ACAT1 was higher in various tumor cells, even though the levels of ACAT1 protein were similar. The reason is that proteins cluster together in cancer cells and become tetramers. Tyrosine kinases, which are usually hyperproliferative in cancer cells, "hijack" ACAT1 and turn it into a tetramer, making them more enzymatically active. This suggests that ACAT1 is a good anti-cancer target.
Figure 1. ACAT1 in tumor. (Fan, J., et al. 2016)
ACAT1 and Neurological Diseases
Niemann-Pick disease, also known as sphingomyelinosis, is a congenital metabolic disease of glycolipids. It is characterized by a large number of foam cells containing sphingomyelin in mononuclear macrophages and nervous systems. Niemann-Pick's disease (NPC), a hereditary lysosomal storage disease with the progressive neurodegenerative disease, is caused by a deficiency in NPC1 protein. The FC produced by the late endosome (LE) is transported to the cell membrane by the transporter NPC1 / NPC2, and the excess FC is further transported to the endoplasmic reticulum, which is catalyzed by the ACAT1 located in the endoplasmic reticulum. Therefore, modified or natural LDL-derived FC is re-esterified in the endoplasmic reticulum, released into the cytosol, and stored as lipid droplets, which are processes that form foam-like transformed macrophages. The lack of NPC1 protein causes FC accumulation in LE and inhibits acid sphingomyelinase. That is, NPC causes accumulation of FC and sphingomyelin, leading to cytotoxicity. One strategy for treating NPC is to use methyl-β-cyclodextrin to remove LE and FC on the cell membrane.
ACAT1 and Atherosclerosis
Hepatic stellate cells (HSC) play an important role in the development of liver fibrosis. When ACAT1 is missing, FC accumulates in the HSC. Then increase the protein level of Toll-like receptor 4 (TLR4) on the membrane and promote TLR4 signaling. Thus, bone morphogenetic protein and activin membrane-binding inhibitors are down-regulated, making HSC sensitive to TGF-β, resulting in HSC activation and liver fibrosis.
The main reason for the lack of ACAT1 to aggravate liver fibrosis is the increase in FC in HSC but does not affect CE accumulation. Therefore, regulating the activity of ACAT1 in HSC may be one of the targets for the treatment of liver fibrosis. Studies have shown that increased accumulation of FC in ACAT1-deficient macrophages plays a central role in the progression of atherosclerosis. Excessive accumulation of intracellular FC is cytotoxic, and accumulation of FC in the ER membrane increases ER stress, leading to apoptosis of macrophages in vitro and in vivo. These results suggest that reducing ACAT1 activity may be mediated by increasing intracellular FC accumulation rather than reducing CE content.
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