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ACAT2 is acetyl-CoA acetyltransferase 2. The human ACAT2 gene is located at 12q13.3-q15 and consists of 15 exons and 13 introns. The full length is about 18 kb. All exon/intron junction sequences are classical GT/AG sequences. ACAT2 is mainly distributed in the hepatocytes and the top of the epithelial cells of the small intestine. It catalyzes the connection of cholesterol with long-chain fatty acids to form cholesterol esters, which plays an important role in the absorption, transportation, and storage of cholesterol in the body.
Figure 1. The protein–protein interactions of ACTA2 and other lipid metabolism enzymes or proteins. (Zhao, et al. 2015).
In liver and small intestinal cells, ACAT2 is involved in lipoprotein assembly. The role of ACAT2 in hepatocytes is to protect cells from excess cholesterol. ACAT2 catalyzes the synthesis of cholesterol esters and triacylglycerols, which are transported by microsomal triglyceride transporters to apolipoprotein B, followed by cholesterol, phospholipids and other apolipoproteins assemble into very low-density lipoproteins that are secreted from the liver into the bloodstream.
Some researchers used antisense oligonucleotide technology to knock down the ACAT2 gene in mouse liver and found that inhibiting liver ACAT2 activity can reduce the production of cholesterol esters in the liver and apolipoprotein B and the secretion of lipoprotein (very low-density lipoprotein, medium-density, and low-density lipoproteins), and high-density lipoprotein levels remain unchanged. At the same time, it was found that the excretion of neutral sterols in the intestine increased and the sterols excreted in the bile remained unchanged. This reveals the esterification pathway of cholesterol in the liver and its excretion pathway, that is, excretion by the intestine rather than bile excretion. ACAT2 in small intestinal cells esterifies cholesterol to maintain a low concentration of free cholesterol to facilitate the diffusion of cholesterol from the intestinal lumen into cells. Guo et al found that ACAT2 expression in human leukocytes controls the excretion of cholesterol/sterol ester (CE/SE)-containing lipoproteins. Excretion of lipoproteins containing ACAT2-catalyzed CS/SE can avoid cytotoxicity by reducing excess intracellular cholesterol/sterols (especially various oxysterols), which plays an important role in the metabolism of human leukocytes.
He et al. found two human ACAT2 gene polymorphisms, 41A>G (Glu(14)Gly, rs9658625) and 734C>T (Thr(254)IIe, rs2272296)have significant an effect on plasma lipid levels and coronary artery disease by case-control association studies. The results of the study showed that the enzyme activity of the mutant Glu(14)Gly was about two times higher than that of the wild type, and this increase was mainly caused by an increase in the expression and/or stability of the mutant ACAT2 protein. Therefore, the genetic variation of Glu(14)Gly is functionally important and may contribute to the expression and stability of the ACAT2 protein.
ACAT2 and Atherosclerosis
ACAT is an important enzyme that regulates the balance of cholesterol concentrations in plasma and bile. Excessive cholesterol in the plasma leads to atherosclerosis, and an increase in cholesterol secretion in the bile can cause cholesterol stones. A large number of studies at home and abroad have shown that ACAT plays a crucial role in the pathogenesis of atherosclerosis. The most direct and powerful evidence comes from gene knockout experiments. The researchers found that ACAT2-/- mice had decreased cholesterol-absorbing capacity and reduced blood cholesterol levels, as well as for gallstone disease and food-induced hypercholesterolemia in mice with ACAT2 gene knockout (ACAT2-/-). Therefore, it is speculated that specific inhibition of ACAT1 will disrupt the intracellular cholesterol metabolism balance, leading to the cytotoxic effect of cholesterol and not conducive to the prevention of atherosclerosis. Specific inhibition of ACAT2 expression and activity will reduce cholesterol absorption and transport. Moreover, it does not affect the balance of intracellular cholesterol metabolism. It is an effective target and promising treatment measures for preventing hyperlipidemia and atherosclerosis.
ACAT2 and Tumor
Studies have shown that prostate cancer is an androgen-dependent disease and is associated with high cholesterol levels. By studying the activity and expression of ACAT in cholesterol metabolism of prostate cancer LNCaP and PC-3 cell lines, it was found that in PAR+ cells, the expression of androgen receptor and ACAT1 protein decreased, cholesterol level decreased, and the expression of ACAT2 remained unchanged. This reveals the importance of regulation of cholesterol metabolism in prostate cancer cells.
In addition, in adult liver, hepatocyte nuclear factor (HNF1α) is a trans-acting factor of the liver-specific ACAT2 gene. When combined with a site on the ACAT2 gene, it can significantly up-regulate the expression of ACAT2 in the liver. LBL laboratory using human liver tissue, liver cancer, and adjacent tissues, combined with a variety of human liver cell lines, showed that human liver cell line, liver tissue, liver cancer and paracancerous tissues all expressed HNF1α. The expression of Cdx2 and ACAT2 wasn't observed in human normal liver cell line LO2 and liver tissue. In the tumor cell line HepG2, both Cdx2 and ACAT2 were expressed. In 50% of patients with liver cancer, the results of adjacent tissues were consistent with those of normal liver cell line LO2 and liver tissue. The results of cancer tissue detection were consistent with the above-mentioned tumor cell line HepG2, indicating that the expression of ACAT2 gene in liver cancer is closely related to the high expression of Cdx2.
These findings not only clarify the molecular mechanism of hepatocyte tissue-specific expression of ACAT2 gene for the first time but also suggest that ACAT2 can be used as a new potential biomarker molecule for detecting liver cancer. Huang et al. found that ACAT2 may affect cancer progression by activating leptin receptor through analyzing tissue samples from primary breast cancer. The data suggest that leptin may enhance the proliferation, migration, and invasion of breast cancer cells through up-regulation of ACAT2. Therefore, the leptin/ACAT2 axis may be a therapeutic target for breast cancer, especially in postmenopausal and/or obese women.