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Published on: October 6, 2014
Lovastatin, but not orlistat, reduces intestinal polyp volume in an ApcMin/+ mouse model
Maria Notarnicola1, Michele Barone2, Antonio Francavilla2
1Laboratory of Nutritional Biochemistry, National Institute for Digestive Diseases 'S. de Bellis', Castellana Grotte, Bari, Italy.
Abstract:
The statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) and orlistat, an inhibitor of fatty acid synthase (FAS), inhibit tumor cell growth by restricting cholesterol and fatty acid synthesis, respectively. We previously demonstrated that an omega (ω)-3 polyunsaturated fatty acid (PUFA)- or olive oil-enriched diet reduced the polyp number and volume in ApcMin/+ mice. This phenomenon was associated with a significant inhibition of FAS and HMGCoAR, as well as an increase in the estrogen receptor (ER)β/α ratio. Herein, we evaluated the effect of lovastatin and orlistat on polyp development and ER expression in ApcMin/+ mice, in order to confirm previous data obtained with ω‑3-PUFAs and olive oil. As expected, the use of lovastatin and orlistat significantly reduced HMGCoAR and FAS enzymatic activities and gene expression in colonic tissues, but did not affect the number of intestinal polyps, while there was a statistically significant reduction in polyp volume only in the mouse group treated with lovastatin. In the mice receiving orlistat, we observed a significant increase in cell proliferation in the polyp tissue, as well as enhanced expression of ERα. Moreover, the overexpression of ERα was associated with a statistically significant increase in PES1, Shh and Gli1 protein levels, considered ERα-related molecular targets.
Insights
Lovastatin and orlistat, which inhibit cholesterol and fatty acid synthesis, reduced tumor-related enzyme activity in mice. Lovastatin decreased polyp volume, while orlistat increased cell proliferation and estrogen receptor alpha expression.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Statins (HMGCoAR inhibitors) and orlistat (FAS inhibitor) restrict tumor cell growth by limiting cholesterol and fatty acid synthesis.
- Previous studies showed ω-3 PUFA or olive oil diets reduced polyps in ApcMin/+ mice by inhibiting FAS and HMGCoAR, increasing the ERβ/α ratio.
Purpose of the Study:
- To evaluate the effects of lovastatin and orlistat on intestinal polyp development and estrogen receptor (ER) expression in ApcMin/+ mice.
- To confirm previous findings with ω-3 PUFAs and olive oil in a mouse model of intestinal polyposis.
Main Methods:
- ApcMin/+ mice were treated with lovastatin or orlistat.
- Enzymatic activities and gene expression of HMGCoAR and FAS in colonic tissues were measured.
- Polyp number, volume, cell proliferation, and ERα and ERβ expression were assessed.
- Protein levels of ERα-related molecular targets (PES1, Shh, Gli1) were analyzed.
Main Results:
- Lovastatin and orlistat significantly reduced HMGCoAR and FAS activities and gene expression.
- Neither drug affected the number of intestinal polyps.
- Lovastatin treatment led to a statistically significant reduction in polyp volume.
- Orlistat treatment resulted in increased cell proliferation and enhanced ERα expression in polyps.
- Overexpression of ERα was linked to increased PES1, Shh, and Gli1 protein levels.
Conclusions:
- Lovastatin demonstrates potential in reducing intestinal polyp volume by inhibiting HMGCoAR.
- Orlistat's effect on ERα expression and cell proliferation warrants further investigation in the context of tumor development.
- Targeting cholesterol and fatty acid synthesis pathways offers distinct outcomes in ApcMin/+ mouse models.
