The role of HIF-1a in the development of an imbalance of carnitine metabolism in severe COVID-19 pneumonia

Introduction. Severe forms of COVID-19 pneumonia are associated with hypoxia, which increases inflammation and hemostasis disorders. HIF-1a plays a central role in the response to hypoxic conditions, which reprograms metabolism by inhibiting the tricarboxylic acid cycle and stimulating lactate production, leading to the accumulation of acetyl-CoA and activation of CRAT. Paradoxically, HIF-1a suppresses CPT1A, disrupting the β-oxidation of fatty acids. Dysregulation of carnitine-dependent fatty acid transport in COVID-19 has not been sufficiently studied. We suggest that HIF-1a-mediated suppression of CPT1A and the release of CRAT from damaged cells cause carnitine imbalance.

Aim of the study – comprehensive analysis of the carnitine profile and CRAT level in severe COVID-19 pneumonia.

Material and Methods. The retrospective study included 30 people: 22 patients with COVID-19 pneumonia and 8 healthy volunteers. Patients with COVID-19 were divided according to the severity of the disease (moderate – 8, severe – 7, extremely severe – 7). The concentrations of total, free, and acylcarnitines in blood plasma were determined (calculated) by the L. Wan and R.W. Hubbard method on an enzyme immunoassay analyzer (410 nm). The levels of HIF-1a and CRAT in blood plasma were determined using competitive enzyme immunoassay.

Results. In patients with COVID-19 pneumonia, there was a significant increase in free carnitine (p=0.029) and a decrease in total carnitine (p=0.043) and acylcarnitines (p=0.016), as well as an increase in CRAT (p=0.028) compared with the group of healthy volunteers. In the extremely severe course of COVID-19 pneumonia, the CRAT level is elevated. The level of CRAT in blood plasma positively correlated with the severity of the condition (r=0.533, p<0.05) and the duration of ICU stay (r=0.588, p<0.01), and negatively with SPO₂ (r=-0.498, p<0.05), ROX index (r=-0.6, p<0.01) and the concentration of HIF-1a (r=-0.651, p<0.05). Free carnitine inversely (r=-0.487, p<0.05), and acylcarnitines directly (r=0.501, p<0.05) correlated with the duration of hospitalization. Total carnitine was inversely dependent on the ROX index (r=-0.588, p<0.01).

Conclusions. Carnitine imbalance was detected in patients with COVID-19 pneumonia, probably due to HIF-1a-induced beta-oxidation disorder. The level of CRAT in blood plasma is potentially a predictive marker of the severity of metabolic stress and hypoxia. Correlations of the carnitine profile with the duration of hospitalization and ROX emphasize the clinical significance of these indicators and require further study.