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.