The mechanism by which HnRNPF affects small intestinal fat absorption by regulating the expression of Acsl5 and Gpat3

Intestinal lipid absorption is essential for dietary lipid uptake. Dietary triacylglycerol (TAG) is hydrolyzed by pancreatic lipase into free fatty acids (FFA) and monoacylglycerol (MAG). These products enter intestinal epithelial cells, where re-esterification (via MGAT, GPAT, and DGAT) regenerates TAG for systemic transport.This process requires FATPs for lipid uptake and ACSLs for FFA activation. Dysregulation of these enzymes or dietary extremes disrupts lipid homeostasis, contributing to metabolic diseases (e.g., fatty liver, obesity, diabetes, atherosclerosis). Studying enzyme regulation is critical for understanding lipid metabolism and disease mechanisms.HnRNPF, a member of the heterogeneous nuclear ribonucleoprotein (HnRNP) family, has been shown to regulate mRNA splicing, stability, nuclear export, and translation efficiency by binding to G-rich elements or G-quadruplexes in the mRNA molecules, thereby influencing cell proliferation and differentiation. HnRNPF is widely expressed in various tissues throughout the body. Bioinformatics analysis indicates that it is highly expressed in the small intestine, and RNA sequence analysis reveals potential HnRNPF binding sequences in the 5'UTR of ACSL5 and GPAT3 mRNAs. However, whether HnRNPF regulates the expression of ACSL5 and GPAT3 by binding to their mRNAs and thereby affects intestinal fat absorption and its downstream effects remains to be explored.This study utilized HnRNPF-specific knockout mice in intestinal epithelial cells (Villin-Cre;HnRNPFF/F, HnRNPF cKO) to investigate the regulatory role and mechanism of HnRNPF in intestinal fat absorption and its impact on high-fat diet-induced fatty liver and obesity. The results indicate that HnRNPF in intestinal epithelial cells can promote the stability of Acsl5 and Gpat3 mRNA, thereby promoting their expression, and thereby promoting the re-synthesis of triglycerides in the intestine after meals to promote fat absorption, and can also affect the lipid homeostasis of the liver and peripheral adipose tissue. These studies not only provide a new perspective on the mechanism of intestinal fat absorption, but also provide experimental evidence for the intervention of related metabolic diseases or other research.