Evolutionary conservation and divergence of regional fructose-responsive gene regulation in the intestine

Sugar-responsive gene regulation in peripheral organs facilitates safe utilization of fructose. Intestine is the first-line site for fructose catabolism, converting fructose into less harmful metabolites. Its metabolism is spatially organized along the proximodistal axis, but how intestinal zonation shapes responses to fructose and to what extent these responses are evolutionarily conserved remain poorly understood. Here, we examine regional gene regulation in response to acute fructose challenge across the small intestine of mouse and Drosophila. Fructose exposure elicited both ubiquitous and regionally biased regulation of metabolic genes. Unlike prolonged feeding on a complex high-carbohydrate diet, fructose feeding activated the heat shock and immune responses, with proximal and distal biases, respectively. The ChREBP/Mondo-Mlx pathway emerged as the major regulator of fructose-responsive gene expression, with a conserved role in regulation of both ubiquitous and region-restricted metabolic targets. Comparative analysis of orthologous genes revealed conserved activation of glucose metabolism, nutrient transport, and stress-responsive pathways, but also notable divergence in downstream metabolic programs. Whereas mouse intestine activates pathways required for fructose conversion into glucose, Drosophila preferentially activates de novo lipogenesis. Thus, intestinal gene regulation provides a conserved protective mechanism against high fructose challenge, but the pathways involved have partially diverged during evolution.