Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes.
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-kappaB) 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-kappaB 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.


CONCLUSIONS
Unsaturated fatty acids inhibit PTEN expression in hepatocytes by up-regulating microRNA-21 synthesis via an mTOR/NF-kappaB-dependent 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.
Vinciguerra
Manlio
M
Department of Cellular Physiology and Metabolism, Geneva Medical Faculty, Switzerland.
Sgroi
Antonino
A
Veyrat-Durebex
Christelle
C
Rubbia-Brandt
Laura
L
Buhler
Leo H
LH
Foti
Michelangelo
M
D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D019301:Oleic Acid / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D058570:TOR Serine-Threonine Kinases; D051996:Transcription Factor RelA / Q000378:metabolism; D015854:Up-Regulation
D005230:Fatty Acids, Nonesterified; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D019301:Oleic Acid; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase