Liraglutide has been demonstrated to alleviate hepatic steatosis in clinical practice, but the underlying mechanism remains unclear. Our previous study indicated that the HIF-2α/PPARα pathway was involved in hepatic lipid accumulation induced by hypoxia.We aimed to investigate whether liraglutide could alleviate lipid-induced hepatic steatosis via the HIF-2α/PPARα pathway. Whole-body HIF-2α heterozygous knockout (HIF-2α^+/-) mice and littermate wild-type (WT) mice were successfully established. Male mice challenged with a high-fat diet were treated with liraglutide (0.6 mg/kg/d) or normal saline by intraperitoneal injection for 4 weeks. We observed that, compared with WT mice, many indicators of HIF-2α^+/- mice improved, including GTT, ITT, fasting blood glucose, body weight, liver weight, and lipid profile in serum or liver lipid deposition, and the expression level of PPARα, mitochondrial function genes, and fatty acid oxidation genes were upregulated, while those of HIF-2α and lipogenesis genes were downregulated significantly. After liraglutide treatment in WT mice, we found that significant improvements were observed in the fat mass, GTT, ITT, fasting blood glucose, body weight, liver weight, lipid profile in serum or liver lipid deposition; the β-oxidation genes were upregulated and the lipogenesis genes were downregulated; and the abundance of intestinal Akkermansia muciniphila increased significantly. However, the effects of liraglutide on WT mice were not observed in HIF-2α^+/- mice. In addition, in the HepG2 steatotic hepatocyte model, liraglutide alleviated lipid deposits by repressing lipid synthesis and enhancing fatty acid β-oxidation, which were substantially suppressed by the HIF-2α modulators. Therefore, the HIF-2α/PPARα pathway is essential for liraglutide-alleviated lipid-induced hepatic steatosis.

在临床实践中，利拉鲁肽已被证明可减轻肝脂肪变性，但其潜在机制尚不清楚。我们之前的研究表明HIF-2α/PPARα通路参与了缺氧诱导的肝脏脂质积累。我们旨在研究利拉鲁肽是否可以通过HIF-2α/PPARα通路减轻脂质诱导的肝脏脂肪变性。成功建立了全身 HIF-2α 杂合敲除 (HIF-2α ^+/- ) 小鼠和同窝野生型 (WT) 小鼠。用利拉鲁肽 (0.6 mg/kg/d) 或生理盐水腹腔注射治疗高脂肪饮食的雄性小鼠 4 周。我们观察到，与 WT 小鼠相比，HIF-2α ^{+/- 的}许多指标小鼠的 GTT、ITT、空腹血糖、体重、肝脏重量、血脂谱或肝脏脂质沉积等改善，PPARα、线粒体功能基因、脂肪酸氧化基因的表达水平上调，而HIF-2α 和脂肪生成基因显着下调。在 WT 小鼠中，利拉鲁肽治疗后，我们发现脂肪量、GTT、ITT、空腹血糖、体重、肝脏重量、血清脂质谱或肝脏脂质沉积有显着改善；β-氧化基因上调，脂肪生成基因下调；肠道Akkermansia muciniphila的丰度显着增加。然而，在 HIF-2α ^+/-中未观察到利拉鲁肽对 WT 小鼠的影响老鼠。此外，在 HepG2 脂肪变性肝细胞模型中，利拉鲁肽通过抑制脂质合成和增强脂肪酸 β-氧化来减轻脂质沉积，这被 HIF-2α 调节剂显着抑制。因此，HIF-2α/PPARα途径对于利拉鲁肽缓解的脂质诱导的肝脂肪变性是必不可少的。