Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism

Abstract

The liver is the major metabolic hub, ensuring appropriate nutrient supply during fasting and feeding. In obesity, accumulation of excess nutrients hampers proper liver function and is linked to non-alcoholic fatty liver disease. Understanding the signaling mechanisms that enable hepatocytes to quickly adapt to dietary cues, might help to restore balance in liver diseases. Post-translational modification by attachment of the Small Ubiquitin-like Modifier (SUMO), allows for a dynamic regulation of numerous processes including transcriptional reprograming. Here, we demonstrate that the specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 was highly modified by SUMOylation on lysine 556 in the liver of ad libitum and re-fed mice, while this modification was strongly abolished upon fasting. In a context of diet-induced obesity, Prox1 SUMOylation became insensitive to fasting cues. Hepatocyte-selective knock in of a SUMOylation-deficient Prox1 mutant into mice fed a high fat/high fructose diet led to reduction of systemic cholesterol levels, associated with the induction of bile acid detoxifying pathways in mutant livers during fasting. As appropriate and controlled fasting protocols have been shown to exert beneficial effects on human health, tools to maintain the nutrient-sensitive SUMOylation switch on Prox1 may thus contribute to the development of "fasting-based" approaches for the maintenance of metabolic health.