The role of apolipoprotein E in gallstone disease, colorectal cancer and gastrointestinal cell regulation

Abstract

Apolipoprotein E (apo E) is one of the key regulatory proteins in cholesterol and lipoprotein metabolism. The present research focuses on the role of apo E in gastrointestinal diseases. The polymorphism of apo E has been suggested to be associated with the cholesterol content in gallstones and the crystallization rate of gallbladder bile. The possible effect of apo E polymorphism on the susceptibility to gallstone disease at the population level was examined in comparison with the classical risk factors for gallstone disease. The data suggest that the apolipoprotein E2 isoform is a genetic factor that provides protection against gallstone disease in women.

The alterations in plasma lipoprotein levels and bile acid metabolism observed in patients with colorectal adenoma and carcinoma may reflect a genetic background predisposing to tumors through altered lipid metabolism. To determine, whether the polymorphism of apo E is associated with proximal or distal colonic neoplasia, the apo E phenotype was determined in 135 patients with colorectal carcinoma, and 199 randomly selected control subjects. The frequency of the ε4 allele of apo E was low in the patients with proximal adenoma and those with carcinoma, respectively, compared with the control subjects. The patients with distal tumors showed no alteration in ε4 frequency. The data suggest that the ε4 allele of apo E provides protection against the development of adenoma and carcinoma of the proximal colon. The association of apo E polymorphism with tumors is not a generalized phenomenon as is shown by the lack of association with breast or prostate cancers.

To further study the mechanisms by which apo E might affect colon cancer, the expression of apo E in human intestine and the localization of apo E in normal and malignant gastrointestinal tract was studied using immunohistochemistry and in situ hybridization. Both immunoreactive apo E protein and apo E mRNA were present throughout the stomach, small intestine and colon. The phagocytes of lamina propria were positive for apo E, but the number of positive cells and the staining intensity varied according to localization. Macrophages in the superficial lamina propria of normal colon were more strongly positive for apo E than those in the small intestine, where the most positively stained cells were dendritic cells and macrophages in the germinal centers of lymphoid follicles. In samples from colorectal carcinomas intensely positive macrophages surrounded the tumor area, suggesting that apo E might play a role in the proliferation of malignant cells.

Apo E binds with very high affinity to heparin and proteoglycans and inhibits the proliferation of several cell types, but the antiproliferative mechanism of apo E is still largely unknown. The effects of apo E at the cellular levels were studied in cell culture experiments. The effect of recombinant human apo E3 on cell polarity and the distribution of β-catenin were examined in undifferentiated (G+) and differentiated (G+ reversed) HT29 human colon adenocarcinoma cell lines. In cultured undifferentiated HT29 cells, treatment with apo E improved cell polarity and translocated β-catenin from the cytoplasm to cell-cell adhesion sites. Apo E may thus modulate epithelial integrity and contribute to cell growth and malignant transformation.