A pathway involving farnesoid X receptor and small heterodimer partner positively regulates hepatic sirtuin 1 levels via microRNA-34a inhibition.
Sirtuin 1 (SIRT1) is a NAD-dependent deacetylase that is critically involved in diverse cellular processes including metabolic disease, cancer, and possibly aging. Despite extensive studies on SIRT1 function, how SIRT1 levels are regulated remains relatively unknown. Here, we report that the nuclear bile acid receptor farnesoid X receptor (FXR) inhibits microRNA-34a (miR-34a) in the liver, which results in a positive regulation of SIRT1 levels. Activation of FXR by the synthetic agonist GW4064 decreases hepatic miR-34a levels in normal mice, and consistently, hepatic miR-34a levels are elevated in FXR-null mice. FXR induces expression of small heterodimer partner (SHP), an orphan nuclear receptor and transcriptional corepressor, which in turn results in repression of p53, a key activator of the miR-34a gene, by inhibiting p53 occupancy at the promoter. MiR-34a decreased SIRT1 levels by binding to the 3'-untranslated region of SIRT1 mRNA, and adenovirus-mediated overexpression of miR-34a substantially decreased SIRT1 protein levels in mouse liver. Remarkably, miR-34a levels were elevated, and SIRT1 protein levels were reduced in diet-induced obese mice, and FXR activation in these mice reversed the miR-34a and SIRT1 levels, indicating an intriguing link among FXR activation, decreased miR-34a, and subsequently, increased SIRT1 levels. Our study demonstrates an unexpected role of the FXR/SHP pathway in controlling SIRT1 levels via miR-34a inhibition and that elevated miR-34a levels in obese mice contribute to decreased SIRT1 levels. Manipulation of this regulatory network may be useful for treating diseases of aging, such as metabolic disease and cancer.
Lee
Jiyoung
J
Department of Molecular and Integrative Physiology, University of Illinois, Urbana-Champaign, Illinois 61801, USA.
Padhye
Amruta
A
Sharma
Abhilasha
A
Song
Guisheng
G
Miao
Ji
J
Mo
Yin-Yuan
YY
Wang
Li
L
Kemper
Jongsook Kim
JK
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000096:biosynthesis* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D020413:3' Untranslated Regions; D007555:Isoxazoles; D035683:MicroRNAs; D018160:Receptors, Cytoplasmic and Nuclear; D056564:Sirtuin 1; D016159:Tumor Suppressor Protein p53; D000099150:Receptor, Farnesoid X-Activated; C522425:MIRN34 microRNA, human; C495901:TP53 protein, human; C099713:nuclear receptor subfamily 0, group B, member 2; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; C412815:GW 4064