A master regulator of lipid metabolism acting through protein denitrosylation, Venetos et al.

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Lipid homeostasis is subject to control by master regulators such as sirtuin deacetylases that reverse CoA-dependent acetylation. Here we show that a mammalian denitrosylase (SCoR2), which counteracts CoA-dependent S-nitrosylation, serves as a major regulator of both fat storage and lipogenesis to control metabolic health. In mice, SCoR2 expression correlates with body mass, and deleting or drugging SCoR2 prevents both diet-induced obesity and fatty liver (MASLD). Loss of SCoR2 in adipocytes promotes S-nitrosylation of Myosin 9, inhibiting transcription factors PPAR, SREBP1 and CEBP to limit fat storage, while in hepatocytes, SCoR2-regulated S-nitrosylation of lipogenic enzymes reduces fat synthesis and induces fat oxidation. In humans, an obesity-linked polymorphism increases SCoR2 expression, and in patient adipose and liver tissues, SCoR2 expression level directly correlates with adipocyte size and MASLD. SCoR2 is therefore a key regulator of nutrient metabolism, akin to sirtuins, and a potential drug target for obesity and MASLD. Raw data files for publication figures and for proteomics

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