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.