Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, Kentucky, USA.
Department of Medicine, Division of Environmental Medicine, Center for Cardiometabolic Science, Christina Lee Brown Envirome Institute, University of Louisville School of Medicine, Louisville, Kentucky, USA.
Hepatol Commun. 2024 Nov 25;8(12). doi: 10.1097/HC9.0000000000000572. eCollection 2024 Dec 1.
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.
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.
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.
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.
肠道上皮缺氧诱导因子-1α（HIF-1α）在维持肠道屏障功能中起着关键作用。本研究旨在确定肠道 HIF-1α 的药理学或遗传学激活是否可以改善西式饮食引起的代谢功能障碍相关脂肪性肝病。
通过二甲氧酰基甘氨酸（dimethyloxalylglycine）对 HIF-1α 的药理学激活作用，在 HIF-α 荧光素酶报告基因（ODD-luc）小鼠中进行了评估。雄性和/或雌性肠上皮特异性 Hif1α 过表达小鼠（Hif1αLSL/LSL;VilERcre）及其野生型同窝小鼠（Hif1αLSL/LSL）分别给予常规饮食、高果糖（HFr）或高脂肪（60%卡路里）高果糖饮食（HFHFr）8 周。分析代谢表型。
二甲氧酰基甘氨酸处理可增加雄性 ODD-luc 小鼠 HFr 饮食时的肠道 HIF-α 荧光素酶活性和降低血糖水平。雄性 Hif1αLSL/LSL;VilERcre 小鼠对 HFr 饮食的葡萄糖耐量明显优于 Hif1αLSL/LSL 小鼠。8 周 HFHFr 喂养导致 Hif1αLSL/LSL;VilERcre 和 Hif1αLSL/LSL 小鼠肥胖。然而，与雄性 Hif1αLSL/LSL 小鼠相比，雄性 Hif1αLSL/LSL;VilERcre 小鼠肝脏脂肪变性明显减轻，肝脏大小和重量减小。此外，与雄性 Hif1αLSL/LSL 小鼠相比，雄性 Hif1αLSL/LSL;VilERcre 小鼠 HFHFr 诱导的全身炎症反应减轻，而雌性小鼠则没有这种反应。回肠 RNA-seq 分析显示，雄性 Hif1αLSL/LSL;VilERcre 小鼠糖酵解/糖异生增加，上皮细胞增殖增加。此外，体外研究表明，HIF 稳定增强肠类器官的糖酵解。
我们的数据提供了证据，表明肠道 HIF-1α 的药理学或遗传学激活以性别依赖的方式显著改善西式饮食引起的代谢功能障碍相关脂肪性肝病。潜在的机制可能归因于 HIF-1α 激活诱导的糖酵解上调，进而导致上皮细胞增殖增强和肠道屏障功能增强。
