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.

Serum Renin Levels Increase With Age in Boys Resulting in Higher Renin Levels in Young Men Compared to Young Women, and Soluble Angiotensin-Converting Enzyme 2 Correlates With Renin and Body Mass Index

“…A complementary explanation to the association between sACE2 and BMI in males could be that ACE2 gene expression may be upregulated in obesity. In a recent publication, ACE2 gene expression was found to be higher in the lung of obese mice, and in lung epithelial cells of obese subjects, compared to non-obese subjects (Al Heialy et al, 2020 ).…”

Aging, Immunity, and COVID-19: How Age Influences the Host Immune Response to Coronavirus Infections?

“…Once inside cells, it replicates and new viral particles release from cells and invade neighboring cells and extracellular spaces and cause tissue damage leading to clinical signs and symptoms. Besides the lung, the ACE2 receptor is highly expressed in epithelial cells of the gastrointestinal tract and in other organs including the kidneys, vascular endothelial cells, and other tissues including high expression in adipose tissues ( Hamming et al, 2004 ; Al Heialy et al, 2020 ; Al-Benna, 2020 ; Albini et al, 2020 ; Gu et al, 2020 ; Li et al, 2020 ; Thum, 2020 ; Verdecchia et al, 2020 ; Verma et al, 2020 ). Accordingly, the clinical presentation can vary with respiratory symptoms being most common such as cough, shortness of breath, and fever, but GI symptoms such as diarrhea, nausea vomiting are not uncommon.…”

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“…In the human lungs, ACE2 was also overexpressed exclusively in the epithelial cells. 32 This might be of particular importance in the epidemic of COVID-19 because several fatal cases are linked to damages in the lung epithelial tissue. Kruglikov and Scherer 33 argue that ACE2 is overexpressed in adipocytes and adipocyte-like cells, such as pulmonary lipofibroblasts.…”