Intestine-specific ablation of the Hepatocyte Nuclear Factor 4a (Hnf4a) gene in mice has minimal impact on serum lipids and ileum gene expression profile due to upregulation of its paralog Hnf4g

Abstract

Ablation of the gene encoding the nuclear receptor Hepatocyte Nuclear Factor 4a (Hnf4a) in the liver strongly affects HDL concentration, structure and functionality but the role of this receptor in the intestine, the second organ contributing to serum HDL levels, has been overlooked. In the present study we show that mice with intestine-specific ablation of Hnf4a (H4IntKO) had undetectable levels of ΗΝF4A in ileum, proximal and distal colon but normal expression in liver. H4IntKO mice presented normal serum lipid levels, HDL-C and particle size (α1-α3). The expression of the major HDL biogenesis genes Apoa1, Abca1, Lcat was not affected but there was significant increase in Apoc3 as well as in Hnf4g, a paralog of Hnf4a. RNA-sequencing identified metabolic pathways significantly affected by Hnf4a ablation such as type II diabetes, glycolysis, gluconeogenesis and p53 signaling. Chromatin immunoprecipitation assays showed that HNF4G bound to various apolipoprotein gene promoters in control mice but its binding affinity was reduced in the ileum of H4IntKO mice suggesting a redundancy but also a cooperation between the two factors. In the distal colon of H4IntKO mice, where both HNF4A and HNF4G are absent and in a mouse model of DSS-induced colitis presenting decreased levels of HNF4A, most lipoprotein genes were strongly downregulated. In conclusion, Hnf4a ablation in mice does not significantly affect serum lipid levels or lipoprotein gene expression in ileum possibly due to compensatory effects by its paralog Hnf4g in this tissue.