a b s t r a c tFatty liver is strongly associated with metabolic syndrome. Here, we show that the impaired hepatic expression of menin, the product of the MEN1 (multiple endocrine neoplasia type 1) tumor suppressor gene, represents a common feature of several fatty liver mouse models. The liver specific ablation of MEN1 gene expression in healthy mice induced hepatic steatosis under high-fat dietary conditions. Moreover, overexpression of menin in livers of steatotic db/db mice reduced liver triglyceride accumulation. At the molecular level, we found that menin acts synergistically with the nuclear receptor PPARa to control gene expression of fatty acid oxidation. Collectively, these data suggest a crucial role for menin as an integrator of the complex transcriptional network controlling hepatic steatosis. Structured summary of protein interactions:Menin physically interacts with PPAR alpha by anti tag coimmunoprecipitation (View Interaction: 1, 2).

Edited by Laszlo Nagy Keywords: MeninLiver X receptor a Hepatic lipogenesis a b s t r a c t Menin, encoded by the MEN1 gene, was initially identified as a tumor suppressor for endocrine neoplasia. Our previous report showed that Menin enhances PPARa transactivity preventing triglyceride accumulation in the liver. Here, we further explore the role of Menin in liver steatosis. Transient transfection assays demonstrate that Menin inhibits the transcriptional activity of nuclear receptor liver X receptor a (LXRa). Accordingly, Menin overexpression results in reduced expression of LXRa target genes, such as lipogenic enzymes including SREBP-1c, FASN and SCD-1. Co-immunoprecipitation assays revealed physical interaction between Menin and LXRa. Collectively, our data suggest that Menin acts as a novel corepressor of LXRa and functions as a negative regulator of hepatic lipogenesis.