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.
| Identifer | oai:union.ndltd.org:oulo.fi/oai:oulu.fi:isbn951-42-5522-4 |
| Date | 11 January 2000 |
| Creators | Niemi, M. (Mari) |
| Publisher | University of Oulu |
| Source Sets | University of Oulu |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis, info:eu-repo/semantics/publishedVersion |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess, © University of Oulu, 2000 |
| Relation | info:eu-repo/semantics/altIdentifier/pissn/0355-3221, info:eu-repo/semantics/altIdentifier/eissn/1796-2234 |
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