Research Perspective Volume 2, Issue 8 pp 527—534

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.