Regulation of Angiotensin- Converting Enzyme 2 in Obesity: Implications for COVID-19

Abstract

The ongoing COVID-19 pandemic is caused by the novel coronavirus SARS-CoV-2. Age, smoking, obesity, and chronic diseases such as cardiovascular disease and diabetes have been described as risk factors for severe complications and mortality in COVID-19. Obesity and diabetes are usually associated with dysregulated lipid synthesis and clearance, which can initiate or aggravate pulmonary inflammation and injury. It has been shown that for viral entry into the host cell, SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) receptors present on the cells. We aimed to characterize how SARS-CoV-2 dysregulates lipid metabolism pathways in the host and the effect of dysregulated lipogenesis on the regulation of ACE2, specifically in obesity. In our study, through the re-analysis of publicly available transcriptomic data, we first found that lung epithelial cells infected with SARS-CoV-2 showed upregulation of genes associated with lipid metabolism, including the SOC3 gene, which is involved in the regulation of inflammation and inhibition of leptin signaling. This is of interest as viruses may hijack host lipid metabolism to allow the completion of their viral replication cycles. Furthermore, a dataset using a mouse model of diet-induced obesity showed a significant increase in Ace2 expression in the lungs, which negatively correlated with the expression of genes that code for sterol response element-binding proteins 1 and 2 (SREBP). Suppression of Srebp1 showed a significant increase in Ace2 expression in the lung. Moreover, ACE2 expression in human subcutaneous adipose tissue can be regulated through changes in diet. Validation of the in silico data revealed a higher expression of ACE2, TMPRSS2 and SREBP1 in vitro in lung epithelial cells from obese subjects compared to non-obese subjects. To our knowledge this is the first study to show upregulation of ACE2 and TMPRSS2 in obesity. In silico and in vitro results suggest that the dysregulated lipogenesis and the subsequently high ACE2 expression in obese patients might be the mechanism underlying the increased risk for severe complications in those patients when infected by SARS-CoV-2.

Keywords: ACE2; COVID-19; SARS-CoV-2; lipid metabolism; obesity.

FIGURE 1

Heatmap and clustering of SARS-CoV-2 infected healthy epithelial cells versus non-infected (mock-infected cells) using GSE147507 publicly available transcriptomics dataset. Pathways, where the DEGs are involved, are shown on the right side of the heatmap with their adjusted p-value. The C1 represent pathways of genes downregulated in infected cells, while C2 represent pathways of genes upregulated when cells are infected compared to mock-infected cells.

FIGURE 2

Heatmap of top Gene Ontology (GO) of the top DEGs in infected normal epithelium versus mock-infected cells. The bars represent the –log10 of the adjusted p-value for each pathway.

FIGURE 3

PTPRQ and EGR2 are decreased in SARS-CoV-2 infected epithelial cells. Log10 of transcripts counts of the genes related to the regulation of fat cell differentiation IL6, MMP11, ZC3H12A, PTPRQ, and EGR2 in infected cells compared to mock-infected epithelial cells.

FIGURE 4

Leptin signaling pathways genes members and their expression in SARS-CoV-2 infected epithelial cells versus non-infected. Red color signifies upregulation in infected cells, and green signifies downregulation as generated by PathVisio software.

FIGURE 5

Ace2, Srebf1, and Srebf2 expression are differentially expressed in obese mice. Srebf1, Srebf2, and Ace2 mRNA normalized gene expression in response to a high-fat diet in obese compared to regular weight mice extracted from publicly available transcriptomic dataset GSE38092.

FIGURE 6

Expression of ACE2 is highest in lung epithelial cells. mRNA expression of ACE2 was examined in different cell types within the lung using LungGENS web-based tool.

FIGURE 7

Ace2 expression is regulated by SREBP. Normalized mRNA expression of Ace2 gene probes used in the publicly available dataset (GSE31797) comparing SREBP activated with SREBP inhibited alveolar cells.

FIGURE 8

ACE2 expression is decreased in subcutaneous adipose tissue after weight loss. The following publicly available transcriptomic dataset (GSE77962) was explored (25 males; BMI: 28–35 kg/m²), and 28 females (BMI: 28–35 kg/m²) were placed on a very low-calorie diet for 5 weeks and a subsequent weight stable period for 4 weeks.

FIGURE 9

ACE2, TMPRSS2, and SREBP1 expression are increased in lung epithelial cells of obese subjects. Lung epithelial cells from non-obese (n = 4) and obese (n = 3) were used to assess mRNA expression of ACE2 (A), TMPRSS2 (B), and SREBP1 (C). **p < 0.01, ***p < 0.001.

FIGURE 10

Summary of the proposed mechanism of SARS-CoV-2 infection in obese individuals. (1) ACE2 expression is increased in obese subjects due to dysregulation in lipid metabolism. (2) Increased ACE2 expression leads to an increase in the viral entry of SARS-CoV-2, which utilizes ACE2 as a receptor. (3) Upon entry of the virus, dysregulation in lipid metabolism leads to an increase in SREBP, which subsequently leads to a decrease in ACE2 (4). (5, 6) Inhibition of ACE2 activity results in increased lipotoxicity and inflammation. This mechanism demonstrates the dual function of ACE2 in viral infection.