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2014 ; 516
(7529
): 112-5
Nephropedia Template TP
Lee JM
; Wagner M
; Xiao R
; Kim KH
; Feng D
; Lazar MA
; Moore DD
Nature
2014[Dec]; 516
(7529
): 112-5
PMID25383539
show ga
Autophagy is an evolutionarily conserved catabolic process that recycles
nutrients upon starvation and maintains cellular energy homeostasis. Its acute
regulation by nutrient-sensing signalling pathways is well described, but its
longer-term transcriptional regulation is not. The nuclear receptors peroxisome
proliferator-activated receptor-? (PPAR?) and farnesoid X receptor (FXR) are
activated in the fasted and fed liver, respectively. Here we show that both PPAR?
and FXR regulate hepatic autophagy in mice. Pharmacological activation of PPAR?
reverses the normal suppression of autophagy in the fed state, inducing
autophagic lipid degradation, or lipophagy. This response is lost in PPAR?
knockout (Ppara(-/-), also known as Nr1c1(-/-)) mice, which are partially
defective in the induction of autophagy by fasting. Pharmacological activation of
the bile acid receptor FXR strongly suppresses the induction of autophagy in the
fasting state, and this response is absent in FXR knockout (Fxr(-/-), also known
as Nr1h4(-/-)) mice, which show a partial defect in suppression of hepatic
autophagy in the fed state. PPAR? and FXR compete for binding to shared sites in
autophagic gene promoters, with opposite transcriptional outputs. These results
reveal complementary, interlocking mechanisms for regulation of autophagy by
nutrient status.
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