Liver transcriptome analysis of lean mice expressing a SUMO-deficient Prox1 (K556R) mutant in hepatocytes

Accumulation of excess nutrients hampers proper liver function and is linked to non-alcoholic fatty liver disease (NAFLD) in obesity. However, the signals responsible for an impaired adaptation of hepatocytes to obesogenic dietary cues remain still largely unknown. Post-translational modification by the Small Ubiquitin-like Modifier (SUMO), allows for a dynamic regulation of numerous processes including transcriptional reprograming. We demonstrate that specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 is highly SUMOylated on lysine 556 in the liver of ad libitum and re-fed mice, while this modification is abolished upon fasting. In the context of diet-induced obesity, Prox1 SUMOylation becomes less sensitive to fasting cues. The hepatocyte-selective knock-in of a SUMOylation-deficient Prox1 mutant into mice fed a high-fat/high-fructose diet leads to a reduction of systemic cholesterol levels, associated with the induction of liver bile acid detoxifying pathways during fasting. The generation of tools to maintain the nutrient-sensitive SUMO-switch on Prox1 may thus contribute to the development of “fasting-based” approaches for the preservation of metabolic health. Overall design: To explore the function of Prox1 SUMOylation in the liver we generated a conditional hepatocyte specific SUMO-deficient Prox1 (K556R) knock-in mouse model. The expression of Prox1 (K556R) was induced via Cre recombination in 8 weeks old male mice. 11 weeks later, liver samples were collected in the fasted and re-fed states (ZT 15-17) and subjected to RNA-seq analysis.