2 research outputs found
p38/p53/miR-200a-3p feedback loop promotes oxidative stress-mediated liver cell death
<div><p>Although our previous studies have provided evidence that oxidative stress has an essential role in total parenteral nutrition (TPN)-associated liver injury, the mechanisms involved are incompletely understood. Here, we show the existence of crosstalk between the miR-200 family of microRNAs and oxidative stress. The members of the miR-200 family are markedly enhanced in hepatic cells by hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) treatment. The upregulation of miR-200-3p in turn modulates the H<sub>2</sub>O<sub>2</sub>-mediated oxidative stress response by targeting p38α. The enhanced expression of miR-200-3p mimics p38α deficiency and promotes H<sub>2</sub>O<sub>2</sub>-induced cell death. Members of the miR-200 family that are known to inhibit the epithelial to mesenchymal transition (EMT) are induced by the tumor suppressor p53. Here, we show that p53 phosphorylation at Ser 33 contributes to H<sub>2</sub>O<sub>2</sub>-induced miR-200s transcription. In addition, we show that p38α can directly phosphorylate p53 at serine 33 upon H<sub>2</sub>O<sub>2</sub> exposure. Thus, we suggest that in liver cells, the oxidative stress-induced, p38α-mediated phosphorylation of p53 at Ser33 is essential for the functional regulation of oxidative stress-induced miR-200 transcription by p53. Collectively, our data indicate that the p53-dependent expression of miR-200a-3p promotes cell death by inhibiting a p38/p53/miR-200 feedback loop.</p></div
Distinct Plasma Bile Acid Profiles of Biliary Atresia and Neonatal Hepatitis Syndrome
Biliary atresia (BA) is a severe
chronic cholestasis disorder of
infants that leads to death if not treated on time. Neonatal hepatitis
syndrome (NHS) is another leading cause of neonatal cholestasis confounding
the diagnosis of BA. Recent studies indicate that altered bile acid
metabolism is closely associated with liver injury and cholestasis.
In this study, we systematically measured the bile acid metabolome
in plasma of BA, NHS, and healthy controls. Liver bile acids were
also measured using biopsy samples from 48 BA and 16 NHS infants undergoing
operative cholangiography as well as 5 normal adjacent nontumor liver
tissues taken from hepatoblastoma patients as controls. Both BA and
NHS samples had significantly elevated bile acid levels in plasma
compared to normal controls. BA patients showed a distinct bile acid
profile characterized by the higher taurochenodeoxycholic acid (TCDCA)
level and lower chenodeoxycholic acid (CDCA) level than those in NHS
patients. The ratio of TCDCA to CDCA in plasma was significantly higher
in BA compared to healthy infants (<i>p</i> < 0.001)
or NHS (<i>p</i> < 0.001). The area under receiver operating
characteristic curve for TCDCA/CDCA to differentiate BA from NHS was
0.923 (95% CI: 0.862–0.984). These findings were supported
by significantly altered expression levels of bile acid transporters
and nuclear receptors in liver including farnesoid X receptor (FXR),
small heterodimer partner (SHP), bile salt export pump (BSEP), and
multidrug resistant protein 3 (MDR3) in BA compared to NHS. Taken
together, the plasma bile acid profiles are distinct in BA, NHS, and
normal infants, as characterized by the ratio of TCDCA/CDCA differentially
distributed among the three groups of infants