Figure 1.The FXR/SHP pathway controlling miR-34a and SIRT1 expression. Under normal
conditions, activation of FXR signaling induces the metabolic repressor SHP
in liver. SHP is then recruited to the miR-34a promoter and inhibits
binding of the key activator p53 to the DNA, resulting in decreased miR-34a
expression. Inhibition of miR-34a results in increased hepatic SIRT1 levels.
In contrast, under pathophysiological conditions such as fatty livers of
obese mice, the dysregulated FXR/SHP pathway due to highly elevated FXR
acetylation no longer inhibits transcription of miR-34a. The dysregulated
FXR/SHP pathway, along with acetylation of p53 due to cellular stress under
metabolic disease states, result in elevated miR-34a expression, which
contributes to decreased SIRT1 levels.
