COVID-19 and Non-Alcoholic Fatty Liver Disease

Biological Insights From Multi-Omics Data

Carlos J. Pirola; Silvia Sookoian


Liver International. 2023;43(3):580-587. 

In This Article

Abstract and Introduction


We explored the shared pathophysiological mechanisms between COVID-19 and non-alcoholic fatty liver disease (NAFLD) by integrating multi-omics data. We studied common genetic risk factors and underlying biological processes using functional enrichment analysis. To understand the sex-specific pathways involved in the clinical course of SARS-CoV-2 infection, we processed sex-stratified data from COVID-19 genome-wide association datasets. We further explored the transcriptional signature of the liver cells in healthy and COVID-19 tissue specimens. We also integrated genetic and metabolomic information. We found that COVID-19 and NAFLD share biological disease mechanisms, including pathways that regulate the inflammatory and lipopolysaccharide response. Single-cell transcriptomics revealed enrichment of complement-related pathways in Kupffer cells, syndecan-mediated signalling in plasma cells, and epithelial-to-mesenchymal transition in hepatic stellate cells. The strategy of pathway-level analysis of genomic and metabolomic data uncovered L-lactic acid, Krebs cycle intermediate compounds, arachidonic acid and cortisol among the most prominent shared metabolites.


The outbreak of COVID-19 infection represented a challenge of crucial importance for practitioners and public health authorities. The impact of the SARS-CoV-2 infection in patients with underlying chronic non-communicable diseases may be severe, including prolonged hospitalization, systemic complications and risk of death. The worldwide disease outbreak showed that the odds of in-hospital death were higher in patients with metabolic syndrome-associated comorbidities, including obesity, arterial hypertension, diabetes, coronary heart disease[1,2] and non-alcoholic fatty liver disease (NAFLD).[3–7]

In addition, there are sex-specific differences in the course of COVID-19, including differences in severity, case fatality rate and survival between men and women infected with SARS-CoV-2.[8] Among the factors that could explain the sexual dimorphism in patients with COVID-19 are potential sex-related differences in metabolic risk factors, inflammatory response and the systemic stress response regulated by the hypothalamic–pituitary–adrenal axis.[8] Likewise, the sex-related clinical response to SARS-CoV-2 infection could be explained by sex-linked differential expression levels of host receptors for viral cell entry in metabolic tissues such as adipose tissue and/or visceral fat.[9]

There are also important considerations regarding the biology and clinical implications of liver tissue tropism of the novel coronavirus SARS-CoV-2.

Several studies highlighted the presence of liver-related complications in COVID-19 patients that may be explained by diverse mechanisms,[6] including the presence of viral receptors in the host liver[6,10] that might cause direct virus-induced cytopathic injury,[6] cytokine-driven immune-mediated damage,[11] ischemic/hypoxic injury and drug-induced liver injuries.[6]

Chu et al. systematically investigated the cellular susceptibility, species tropism, replication kinetics and cell damage of SARS-CoV-2. They found that of nine tested human cell lines, five were susceptible to SARS-CoV-2 infection, including Caco2 (intestinal) cells, followed by Huh7 (hepatic) and 293 T (renal) cells.[12]

Zhao et al. used human organoids to investigate the SARS-CoV-2 infection and virus-induced tissue damage ex vivo at the cellular and molecular levels. They found consistent evidence that liver damage is caused by direct virus infection in the liver.[13] For instance, SARS-CoV-2 nucleocapsid protein was detected in patchy areas of human liver ductal organoids, and the infected cholangiocytes underwent membrane fusion and formed syncytia.[13] Furthermore, Lui et al. confirmed that cholangiocytes are not only susceptible to SARS-CoV-2 infection, but they also support efficient viral replication by co-expressing angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2).[14]

Analysis of single-cell transcriptomic data originating from non-COVID-19 adult liver specimens showed that ACE2 is expressed in cholangiocytes and hepatocytes.[10] Likewise, TMPRSS2 is expressed in cholangiocytes, hepatocytes, periportal liver sinusoidal endothelial cells, erythroid cells and, to a much lesser extent, in non-inflammatory macrophages and alpha–beta T cells.[10] In addition, all cell types, from hepatocytes to all populations of liver cells, express FURIN.[10]

From the clinical perspective, liver injury was demonstrated in a large proportion of COVID-19-affected patients, and 6%–59% of SARS-CoV-2-infected patients present abnormalities in liver function tests, including elevation in aminotransferases.[6,15] Accordingly, in a clinical series, the proportion of patients admitted with elevated AST, ALT, γ-glutamyl transferase, total bilirubin and alkaline phosphatase was 21.6%, 18.2%, 17.6%, 6.1% and 4.1% respectively.[16]

Collectively, the observations mentioned above support the plausible possibility of shared risk factors and disease mechanisms between COVID-19 and chronic liver diseases, including NAFLD. Hence, in this study, we explored the shared pathophysiological mechanisms between COVID-19 and NAFLD by analysing multi-omics data. We used various bioinformatic and system biology tools and resources that facilitate the integration of high-throughput information derived from large datasets. Furthermore, we focused our study on fundamental research questions with clinical implications, including shared genetic susceptibility of severe COVID-19 and NAFLD and the importance of sexual dimorphism in the disease outcomes. In addition, to understand the potential changes in the transcriptional landscape of the liver cells in healthy and COVID-19 tissue specimens, we analysed the liver cellular heterogeneity depicted by single-cell transcriptomic analysis.