Metabolic dysfunction-associated steatotic liver disease (MASLD) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). Currently, no approved targeted therapeutic interventions exist for MASLD. Hypoxia is known to exacerbate the progression of both MASLD and ASCVD. Notably, peroxisome proliferator-activated receptor α (PPARα), a key regulator of lipid metabolism, has also been implicated in modulating cellular adaptation to hypoxic conditions. This study aims to elucidate the role of PPARα in arterial endothelial cell dysfunction by investigating its involvement in lipid metabolism reprogramming within the context of MASLD under high-altitude hypoxia. We observed that chronic hypoxia exacerbates the increase in low-density lipoprotein (LDL) levels and elevates the risk of ASCVD in MASLD patients. In MASLD mice, chronic hypoxia activates hepatic hypoxia-inducible factor 2-alpha (HIF-2α), which suppresses PPARα, leading to decreased expression of low-density lipoprotein receptor (LDLR) and ATP-binding cassette subfamily G member 8 (ABCG8), consequently raising serum LDL levels and indirectly reducing endothelial nitric oxide synthase (eNOS) expression in arterial endothelial cells. Activation of PPARα can upregulate the expression of LDLR and ABCG8 in hepatocytes, thereby improving fatty liver and restoring the function of aortic endothelial cells. Our study identifies chronic hypoxia induces liver HIF-2α, which inhibits PPARα and impairs hepatic cholesterol metabolism. This leads to MASLD progression and increased ASCVD risk, as impaired cholesterol metabolism negatively affects endothelial cell function. Activation of PPARα enhances hepatic lipid metabolism, thereby indirectly improving endothelial cell function. Moreover, we demonstrate that fenofibrate represents a viable and cost-effective therapeutic strategy for ameliorating MASLD and preventing ASCVD under hypoxic conditions.
Bao et al. (Wed,) studied this question.