Intestine epithelial specific hypoxia-inducible factor-1a overexpression on ileum transcriptome

Background: Intestine epithelial hypoxia-inducible factor-1a (HIF-1a) plays a critical role in maintaining gut barrier function. The aim of this study was to determine genetic activation of intestinal HIF-1a ameliorates western diet-induced metabolic dysfunction–associated steatotic liver disease (MASLD). Methods: Male and/or female intestinal epithelial-specific Hif1a overexpression mice (Hif1a LSL/LSL;VilERcre) and wild-type littermates (Hif1a LSL/LSL) were fed with regular chow diet, high fructose (HFr) or high-fat (60% Kcal) high-fructose diet (HFHFr) for 8 weeks. Metabolic phenotypes were profiled. Results: Male Hif1a LSL/LSL;VilERcre mice exhibited markedly improved glucose tolerance compared to Hif1a LSL/LSL mice in response to HFr diet. Eight weeks HFHFr feeding led to obesity in both Hif1a LSL/LSL;VilERcre and Hif1a LSL/LSL mice. However, male Hif1a LSL/LSL;VilERcre mice exhibited markedly attenuated hepatic steatosis along with reduced liver size and liver weight compared to male Hif1a LSL/LSL mice. Moreover, HFHFr-induced systemic inflammatory responses were mitigated in male Hif1a LSL/LSL;VilERcre mice compared to male Hif1a LSL/LSL mice and those responses were not evident in female mice. Ileum RNA-seq analysis revealed that glycolysis/gluconeogenesis was up in male Hif1a LSL/LSL;VilERcre mice accompanied by increased epithelial cell proliferation. Conclusion: Our data provide evidence that genetic activation of intestinal HIF-1a markedly ameliorates western diet-induced MASLD in a sex-dependent manner. The underlying mechanism is likely attributed to HIF-1a activation induced upregulation of glycolysis, which, in turn, leading to enhanced epithelial cell proliferation and augmented gut barrier function. Overall design: To understand the mechanisms of intestine HIF-1a overexpression on gut barrier function, we performed ileum bulk RNA-seq analysis in male and female Hif1a LSL/LSL and Hif1a LSL/LSL;VilERcre mice [n=3(2 male, 1 female)/group]. Gene expression profile in the mouse ileum was compared between the two groups (Hif1a LSL/LSL versus Hif1a LSL/LSL;VilERcre ie. FLOX_IL versus IECOE_IL)