APOA1

Detailed Information

APOA1 (apolipoprotein A-I) is the major structural protein of high-density lipoprotein (HDL) and is involved in the reverse transport of cholesterol. APOA1 is mainly synthesized in the liver and small intestine. The secondary structure includes 10 characteristic amphipathic α-helical structures, which play an important role in the interaction between APOA1 and lipids. The lipid-free APOA1 first receives free cholesterol in the cells through ABCA1 (ATP binding cassette A1) in peripheral tissue cells and becomes pre-β−HDL. After being remodeled by lecithin cholesterol acyltransferase, phospholipid transfer protein, and cholesterol ester transfer protein, it becomes mature α-HDL. α-HDL continues to collect free cholesterol from peripheral tissues through ABCG1 (ATP binding cassette transporter G1) and finally clears from the blood by the scavenger receptor B1 (SR-B1) expressed by hepatocytes when passing through the liver.

APOA1 mimetic peptides are a class of polypeptides that mimic the lipid transport function of APOA1 by constructing an amphipathic alpha helix structure, which has anti-oxidation, anti-inflammatory and anti-cholesterol reverse transport functions similar to APOA1. It has been successfully applied in a mouse model of atherosclerosis. In recent years, many studies have shown that the reduction of APOA1 levels is closely related to a variety of tumors, and has great potential in early diagnosis, prognosis and therapeutic applications of tumors.

APOA1 and Cardiovascular Disease

Studies by Cedó et al. have demonstrated APOA1-specific autoantibodies and their role in cardiovascular pathophysiology. (a) An atherogenic effect of APOA1-specific autoantibodies in vascular cells. (b) Effect of APOA1-specific autoantibodies on cardiomyocytes. Normally, aldosterone alone is able to increase myocardial pulsation by binding to the mineralocorticoid receptor and further signaling through the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway. (c) Anti-APOA1 antibodies cause HDL dysfunction. In HDL particles, PON-1 can interact with MPO.

Figure 1. ApoA1-specific self-antibodies and their functional effects in cardiovascular pathophysiology (Cedó., et al.2016)

APOA1 has a Tumor-Suppressing Effect

APOA1 has been shown to inhibit the development of various tumors including human tumor cells in vivo and in vitro and to improve the survival prognosis of tumor hosts.

In in vitro cell assays, D-4F and L-4F inhibited proliferation of ID8 cells, cisplatin-resistant human ovarian cancer cells, and mouse colon adenocarcinoma CT26. In animal experiments, APOA1 levels were decreased in murine ovarian cancer mice, and APOA1 overexpressing mice survived longer and had less abdominal metastases. Zamaniandaryoush et al. found that pretreatment with APOA1 in APOA1 knockout mice can prevent the development of melanoma subcutaneous implants, and when tumors are formed, APOA1 can inhibit the further development of tumors and reduce tumor volume. The effect of APOA1 on tumor suppression also showed a dose-dependent effect. Lewis lung cancer has the smallest lesion in human APOA1 homozygous transgenic mice, followed by heterozygous transgenic mice, and APOA1 knockout mice have the largest tumor volume. In addition, APOA1 mimetic peptides can also reduce the tumor burden caused by ID8 ovarian cancer cells.

In spontaneous tumors, the anti-tumor effect of peptidomimetics has also been validated. For example, L-4F can also significantly reduce the size and number of polyps in APCm/+ mice. D-4F showed an effect of inhibiting tumors in a mouse model of PyMT hereditary breast cancer. In PyMT mice, elevated levels of overexpression of APOA1 and HDL did not prevent tumor progression, but treatment with D-4F had an inhibitory effect on tumors, suggesting that there is a difference in the mechanism by which native APOA1 and peptidomimetic inhibit tumors. In addition to murine tumors, APOA1 therapy is equally effective in the nude mouse model of human melanoma A375 subcutaneous xenografts.

Possible Mechanism of Anti-tumor Effect of APOA1 and Its Peptidomimetic

APOA1 and its peptidomimetic can act on cells such as adipocytes and endothelial cells to exert antioxidant effects. Umemoto et al. found that HDL and APOA1 treatment can inhibit the production of reactive oxygen species in adipocytes; others have also reported that the peptide D-4F can promote endothelial repair and reduce oxide production in high cholesterol diet animals. APOA1 and its peptidomimetic also have anti-tumor effects in tumor cells. Cedó et al. found that in the PyMT mouse model, D-4F inhibited the oxidation of low density lipoprotein (LDL) to protect mice from hereditary breast cancer. In this study, overexpression of APOA1 did not inhibit tumors, as high levels of APOA1 caused 27HC levels to rise, and the tumor-promoting effect of 27HC on the estrogen receptor (ER) can counteract the tumor-suppressing effect of APOA1 inhibiting oxidized low-density lipoprotein.

Immunomodulation is one of the important functions of APOA1, and a variety of immune-related receptors are anchored on lipid rafts on the surface of cell membranes. When APOA1 and HDL receive cholesterol from lipid rafts, they can transmit signals to the cells and then exert an anti-inflammatory effect. Abnormal immune surveillance is an important cause of tumorigenesis, so the role of APOA1 in tumor immunity is worth exploring. However, at present, only two studies have reported that APOA1 or peptidomimetic can participate in the regulation of tumor immunity, inhibit tumor invasion, and improve host survival. Neyen et al. found that D-4F can competitively inhibit SRA receptors on the surface of tumor-associated macrophages and inhibit the invasion of ID8 and pancreatic cancer cell line panc02. In a melanoma animal model, overexpression of human APOA1 increases infiltration of type I macrophages, reduces the number of spleen bone marrow-derived suppressor cells (MDSCs) and improves mouse survival.

In order to meet the needs of rapid proliferation, the metabolic pattern of tumor cells is different from normal cells, including abnormal lipid metabolism. APOA1 may participate in the development of tumors by regulating the cholesterol level of cells and participating in the lipid metabolism of cells. The process of APOA1 collecting cholesterol is mediated by ABCA1. Down-regulation of ABCA1 increases mitochondrial cholesterol and promotes tumorigenesis. Studies have found that APOA1 can promote the accumulation of ABCA1 in the ABCA1 cycle and cell membrane, and promote cholesterol efflux. It is speculated that APOA1 may exert an anti-tumor effect through the ABCA1-dependent cholesterol regulation pathway.

Application of APOA1 in Diagnosis, Prognosis, and Treatment

Several studies have explored the diagnostic value and prognosis of APOA1 in tumors. For example, in endometrial cancer, APOA1 combined with prealbumin and transferrin to diagnose early endometrial cancer, with a sensitivity of 71% and a specificity of 88%. For the diagnosis of early ovarian cancer, serum APOA1 levels are superior to CA125 alone in predicting value when used in combination with the other two indicators. In terms of prognostic value, Tuft et al found that patients with ovarian serous adenocarcinoma with high APOA1 mRNA levels in pre-chemotherapy have longer overall survival (OS) and are independent protective factors. Studies in nasopharyngeal carcinoma have found that serum APOA1 ≥ 1.025 g/L is an independent predictor of longer disease-free survival, no local recurrence, and no distant metastasis.