Intestine epithelial-specific hypoxia-inducible factor-1α overexpression ameliorates western diet-induced MASLD.

Background: Intestine epithelial hypoxia-inducible factor-1α (HIF-1α) plays a critical role in maintaining gut barrier function. The aim of this study was to determine whether pharmacological or genetic activation of intestinal HIF-1α ameliorates western diet-induced metabolic dysfunction-associated steatotic liver disease.

Methods: Metabolic effects of pharmacological activation of HIF-1α by dimethyloxalylglycine were evaluated in HIF-α luciferase reporter (ODD-luc) mice. Male and/or female intestinal epithelial-specific Hif1α overexpression mice (Hif1αLSL/LSL;VilERcre) and wild-type littermates (Hif1αLSL/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: Dimethyloxalylglycine treatment led to increased intestine HIF-α luciferase activity and decreased blood glucose levels in HFr diet-fed male ODD-luc mice. Male Hif1αLSL/LSL;VilERcre mice exhibited markedly improved glucose tolerance compared to Hif1αLSL/LSL mice in response to HFr diet. Eight weeks HFHFr feeding led to obesity in both Hif1αLSL/LSL;VilERcre and Hif1αLSL/LSL mice. However, male Hif1αLSL/LSL;VilERcre mice exhibited markedly attenuated hepatic steatosis along with reduced liver size and liver weight compared to male Hif1αLSL/LSL mice. Moreover, HFHFr-induced systemic inflammatory responses were mitigated in male Hif1αLSL/LSL;VilERcre mice compared to male Hif1αLSL/LSL mice, and those responses were not evident in female mice. Ileum RNA-seq analysis revealed that glycolysis/gluconeogenesis was up in male Hif1αLSL/LSL;VilERcre mice, accompanied by increased epithelial cell proliferation. Moreover, an in vitro study showed that HIF stabilization enhances glycolysis in intestine organoids.

Conclusions: Our data provide evidence that pharmacological or genetic activation of intestinal HIF-1α markedly ameliorates western diet-induced metabolic dysfunction-associated steatotic liver disease in a sex-dependent manner. The underlying mechanism is likely attributed to HIF-1α activation-induced upregulation of glycolysis, which, in turn, leads to enhanced epithelial cell proliferation and augmented gut barrier function.