Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes
✍ Scribed by Manlio Vinciguerra; Antonino Sgroi; Christelle Veyrat-Durebex; Laura Rubbia-Brandt; Leo H. Buhler; Michelangelo Foti
- Book ID
- 102850253
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 736 KB
- Volume
- 49
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
Phosphatase and tensin homolog (PTEN) is a regulator of phosphoinositide 3-kinase signaling and an important tumor suppressor mutated/deleted in human cancers. PTEN deletion in the liver leads to insulin resistance, steatosis, inflammation, and cancer. We recently demonstrated that unsaturated fatty acids trigger steatosis by down-regulating PTEN expression in hepatocytes via activation of a mammalian target of rapamycin (mTOR)/nuclear factor kappa B (NF-B) complex, but the molecular mechanisms implicated in this process are still unknown. Here, we investigated potential genetic and epigenetic mechanisms activated by fatty acids leading to PTEN down-regulation. Our results indicate that unsaturated fatty acids down-regulate PTEN messenger RNA expression in hepatocytes through mechanisms unrelated to methylation of the PTEN promoter, histone deacetylase activities, or repression of the PTEN promoter activity. In contrast, unsaturated fatty acids up-regulate the expression of microRNA-21, which binds to PTEN messenger RNA 3-untranslated region and induces its degradation. The promoter activity of microRNA-21 was increased by mTOR/NF-B activation. Consistent with these data, microRNA-21 expression was increased in the livers of rats fed high-fat diets and in human liver biopsies of obese patients having diminished PTEN expression and steatosis. Conclusion: Unsaturated fatty acids inhibit PTEN expression in hepatocytes by up-regulating microRNA-21 synthesis via an mTOR/NF-Bdependent mechanism. Aberrant up-regulation of microRNA-21 expression by excessive circulating levels of fatty acids exemplify a novel regulatory mechanism by which fatty acids affect PTEN expression and trigger liver disorders. (HEPATOLOGY 2009;49:1176-1184.)
P hosphatase and tensin homolog (PTEN) is a protein and phosphoinositide phosphatase originally identified as a tumor suppressor gene frequently mutated/deleted in human cancers. 1 Numerous studies have also strongly supported its role as a regulator of insulin/insulin-like growth factor 1 signaling. In mice, liver-specific PTEN deletion leads to steatosis, insulin hypersensitivity early in life, and hepatomegaly and hepatocellular carcinoma (HCC) at later stages. Consistent with these studies, PTEN is deleted, or weakly expressed, in HCC having a poor prognosis. 5 Interestingly, accumulating evidence indicates that deregulated PTEN expression in hepatocytes, rather than PTEN mutations/ deletions, represents a critical factor in the development of nonalcoholic fatty liver diseases (NAFLD) and HCC. 6,7 PTEN expression is regulated at the posttranscriptional level by various signaling cascades affecting its activity, stability, or intracellular localization. At the transcriptional level, genetic and epigenetic mechanisms