ERBB3 Regulates Lipid Metabolism in the Intestinal Epithelium

Background: ErbB/HER family receptor tyrosine kinases play important roles in intestinal epithelial maintenance and function. ERBB3, in particular, has been identified as a regulator of cell differentiation in this tissue. Interestingly, in preliminary RNA sequencing studies, we observed that ERBB3 deletion leads to changes in expression of lipid uptake and metabolism. As the role of ErbBs in regulating lipid metabolism is poorly understood, we tested the hypothesis that ERBB3 is critical for intestinal lipid uptake and metabolic processing. Methods: Mice with Erbb3 disruption in the intestinal epithelium (Villin-Cre; ErbB3flox/flox; hereafter Erbb3ΔIE) were compared to Erbb3flox/flox littermate controls. Body composition was assessed by EchoMRI, and tissue lipid accumulation was tested by Oil Red O staining. Serum fatty acids and triglycerides were analyzed by mass spectrometry. Ileal scrapings were collected for qRT-PCR and RNA-sequencing analyses. Chromatin accessibility was profiled using ATAC-seq, and associated regulatory elements were linked to nearby genes (≤25 kb) for Gene Ontology pathway analysis. To define signaling mechanisms and identify requisite ErbB heterodimer partners, intestinal enteroids were stimulated with the ERBB3 ligand NRG1 in the presence or absence of PI3K inhibitor LY-294002, ERBB2 inhibitor CP-724714, or EGFR inhibitor PD-174265. Results: Erbb3ΔIE mice exhibited reduced body weight and fat mass compared to controls, accompanied by a marked decrease in enterocyte lipid droplet accumulation. Serum lipidomic profiling revealed extensive alterations in fatty acid and triglyceride species in the Erbb3ΔIE mice. Bulk RNA sequencing of ileal scrapings showed downregulation of key lipid transport genes, including Npc1l1 and Slc27a4, and reduced expression of lipid metabolism regulators Creb3l3, Fabp2, Dgat2, and Apob, along with reduced bile acid transport and intracellular trafficking genes. Furthermore, ATAC-seq revealed that ERBB3 loss leads to widespread chromatin remodeling, including enhancer activation and repression across several loci. Gene ontology analysis of the ATAC-seq data showed enrichment for pathways involved in fatty acid metabolism, cholesterol handling, and chylomicron assembly. In ileal enteroids from control mice, NRG1 induced expression of master lipid regulator Creb3l3 in a PI3K- and EGFR-dependent manner. Conclusion: These findings identify ERBB3, and likely ERBB3-EGFR heterodimers, as a previously unrecognized regulator of intestinal lipid metabolism. This may be mediated by PI3K-dependent regulation of Creb3l3 and chromatin remodeling. Considering the evidence linking disrupted lipid metabolism to conditions such as inflammatory bowel disease, these results point to potential therapeutic interventions targeting epithelial ERBB3-dependent signaling pathways. This research was funded by Senior Research Award from the Crohn’s and Colitis Foundation and NIH award R01DK095004 (MRF). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.