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 (miR34a) 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 miR34a 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.The NAD ϩ -dependent Sirtuin 1 (SIRT1) 3 deacetylase plays a critical role in cellular metabolism, the stress response, and possibly aging, by modulating the activity of its target proteins via protein deacetylation (1-4). Recent studies demonstrate that SIRT1 plays an important role in maintaining metabolic homeostasis in response to hormonal and nutritional fluctuations by modulating the activity of PGC-1␣, a master metabolic regulator (5, 6). During nutritional deprivation, SIRT1 promotes fat mobilization and suppresses adipogenesis and regulates hepatic glucose and lipid metabolism by activating key metabolic regulators, including PGC-1␣ (5, 6). Activation of SIRT1 by natural or synthetic SIRT1 activators reduced acetylation levels of PGC-1␣ and protected against diet-induced obesity and insulin resistance by promoting mitochondrial function (7-9). SIRT1 levels are dynamically regulated in response to fasting and feeding under physiological conditions but markedly reduced in diet-induced obese mice (10). However, the molecular basis by which SIRT1 levels are regulated under normal conditions and why they are substantially reduced in metabolic disease states remains largely unknown.The nuclear receptor, farnesoid X receptor (FXR), is the primary biosensor for endogenous bile acids and regulates expression of numerous genes involved in lipid and glucose metabolism (...