PTEN down-regulation by unsaturated fatty acids triggers hepatic steatosis via an NF-kappaBp65/mTOR-dependent mechanism.
OBJECTIVE
Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a tumor suppressor and a regulator of insulin sensitivity in peripheral tissues. In the liver, PTEN deletion increases insulin sensitivity, but induces steatosis, steatohepatitis, and hepatocellular carcinoma. Here, we investigated the pathophysiologic mechanisms regulating PTEN expression in the liver and the development of steatosis.


METHODS
PTEN expression was evaluated in the liver of rats and human beings having metabolic syndrome. Signaling pathways regulating PTEN expression and lipid accumulation in hepatocytes were examined in vitro.


RESULTS
PTEN expression is down-regulated in the liver of rats having steatosis and high plasma levels of fatty acids, as well as in steatotic human livers. Unsaturated fatty acids inhibited PTEN expression in HepG2 cells via activation of a signaling complex formed by the mammalian target of rapamycin (mTOR) and nuclear factor-kappaB (NF-kappaB). Down-regulation of PTEN expression induced steatosis by affecting import, esterification, and extracellular release of fatty acids.


CONCLUSIONS
Hepatic steatosis can be mediated by alterations of PTEN expression in hepatocytes exposed to high levels of unsaturated fatty acids. Furthermore, our data revealed interaction between mTOR and NF-kappaB, suggesting cross-talk between these 2 pathways.
Vinciguerra
Manlio
M
Department of Cell Physiology and Metabolism, Geneva Medical Faculty, Geneva University Hospital, Switzerland.
Veyrat-Durebex
Christelle
C
Moukil
Moulay Ahmed
MA
Rubbia-Brandt
Laura
L
Rohner-Jeanrenaud
Françoise
F
Foti
Michelangelo
M
D000818:Animals; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005234:Fatty Liver / Q000209:etiology*; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008099:Liver / Q000378:metabolism*; D024821:Metabolic Syndrome / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011494:Protein Kinases / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D051996:Transcription Factor RelA / Q000502:physiology
D005231:Fatty Acids, Unsaturated; D051996:Transcription Factor RelA; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase