4.1.4. Metabolic disorder
Metabolic disorders, including centripetal obesity, hyperlipidemia, hypertension, insulin resistance, and diabetes, are associated with an increased risk of cardiovascular diseases. Evidence from several studies suggests that increased or inhibited interference with exogenous EETs and/or CYP may affect lipid metabolism, which in turn may play a beneficial role in preventing obesity, improving insulin resistance, and treating vascular complications of diabetes.
Hypoxia disrupts metabolic homeostasis and promotes erythropoiesis to adapt to hypoxic environments. Excessive erythropoiesis may trigger chronic altitudinal illnesses. CYP may play a role in hypoxia-associated erythropoiesis: Oguro et al. found that CYP3A4 induced a hypoxic response in Hep3B cells, which was detected as increased expression of erythropoietin genes (Oguro et al., 2011). Xu et al. recruited 63 Tibetan patients with high-altitude erythropoiesis (HAPC) and found that the rs1004467single nucleotide polymorphism (SNP) in the CYP17A1 gene and rs3813865 SNP in the CYP2E1 gene were substantially associated with the risk of HAPC and both SNPs were positively correlated with plasma hemoglobin levels (Xu et al., 2015). To adapt to this change in hypoxic erythrocytes, the synthesis of lipids in the organism is increased to provide more energy and nutrients. The reduced activity of lipase enzymes further contributes to altered lipid metabolism in the organism. This metabolic disturbance is also associated with alterations in CYPs. Piguet et al. found that mice exposed to 10% O2 for seven days had increased erythrocyte pressure volume, increased liver weight/body weight ratio, more pronounced steatosis, higher non-alcoholic fatty liver activity scores, serum aspartate transaminase, triacylglycerol, and glucose, and decreased insulin sensitivity. They also found that CYP2E1 expression increased (Piguet et al., 2009). Notably, some studies have already indicated that CYP2E1 deficiency reduces obesity (Zhang et al., 2022). Although the current study does not definitively indicate whether this metabolic dysfunction under hypoxia is mediated by increased CYP2E1 expression, certainly, CYP is inextricably linked to metabolic dysfunction under hypoxia.