Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a global health concern affecting approximately 25% of the world’s population.
It encompasses a spectrum of liver conditions, from simple steatosis to the more severe non-alcoholic steatohepatitis (NASH), often leading to fibrosis and pre-neoplastic changes. The rise in MASLD is largely attributed to factors such as the Western diet, sedentary lifestyles, and genetic and environmental predispositions.
Although alcohol, viral hepatitis, and autoimmune diseases can coexist with MASLD, the recent adoption of the term “Metabolic Dysfunction-Associated Steatotic Liver Disease” aims to shed light on the primary etiology of this condition, emphasizing its association with metabolic factors.
In this article, we explore recent findings that suggest a connection between MASLD and susceptibility to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, the virus responsible for Coronavirus Disease 2019 (COVID-19). We delve into the intricate interplay between the SARS-CoV-2 virus and the liver, examining the potential implications for patients with MASLD.
The Link Between MASLD and Increased COVID-19 Susceptibility
Recent studies have demonstrated that individuals suffering from metabolic syndrome, NAFLD, or NASH face an elevated risk of liver injury when infected with SARS-CoV-2. Notably, SARS-CoV-2 is known to infect a substantial proportion of patients with comorbidities such as hypertension, metabolic syndrome, and coronary heart disease.
Those who develop severe forms of COVID-19 often experience acute respiratory distress syndrome, immune dysregulation, and a hyperinflammatory state characterized by a “cytokine storm,” which can lead to disseminated intravascular coagulation and blood vessel damage.
ACE2 and Its Role in Liver Infection
The cellular entry of SARS-CoV-2 depends on the binding of the viral spike protein to its specific receptor, Angiotensin-converting enzyme 2 (ACE2), as well as co-receptors such as TMPRSS2, FURIN, and CLEC4M. Importantly, ACE2 is a critical component of the renin-angiotensin-aldosterone system and plays a pivotal role in regulating various physiological processes, including blood pressure, vascular function, and cardioprotection.
While the primary target of SARS-CoV-2 is respiratory cells, evidence has shown that viral particles can be detected in hepatocytes, and viral RNA can be found in portal vein endothelial cells of individuals who succumbed to COVID-19. Furthermore, human liver cells expressing ACE2, such as Huh-7 and HepG2 cells, can be infected with SARS-CoV-2.
Downregulation of ACE2 has been shown to reduce viral infection in human livers. However, the precise cellular localization and expression patterns of ACE2 and co-receptors in MASLD remain unclear.
The renin-angiotensin-aldosterone system’s activation by ACE2 is associated with metabolic and cardioprotective effects, including the regulation of lipid metabolism, mitochondrial function, glucose metabolism, and the reduction of oxidative stress, inflammation, and liver fibrosis. These effects are of particular interest in the context of MASLD, given the role of metabolic disturbances in the pathogenesis of this condition.
Liver Sinusoidal Endothelial Cells (LSECs) and Their Role in Infection
Liver sinusoidal endothelial cells (LSECs) are known for their high endocytic capacity. Together with Kupffer cells, they play a pivotal role in removing antigens, mediating inflammatory responses, and recruiting leukocytes, which amplify local inflammation. Importantly, LSECs are positive for CLEC4M, which plays a key role in capturing viruses. In the case of SARS-CoV-2, CLEC4M has been identified as a receptor recognizing viral particles.
Research Findings in the Context of MASLD
To investigate the potential link between MASLD and COVID-19 susceptibility, researchers conducted a comprehensive study. They constructed a transcriptomic dataset including normal liver samples, steatosis, steatohepatitis, and MASH to assess the expression of ACE2, TMPRSS2, and CLEC4M. The study also explored five additional transcriptomic datasets containing patients with fibroinflammatory liver diseases.
The results showed that individuals with steatohepatitis consistently exhibited increased ACE2 expression in LSECs and hepatocytes. Moreover, ACE2 mRNA expression increased with age in individuals with fatty liver disease, plateauing between 50 and 80 years.
This increase in ACE2 expression correlated with liver fat area, inflammation, immune reactivity, and fibrogenesis. In patients with fibroinflammatory liver diseases, ACE2 expression was upregulated in those who were overweight. Furthermore, in vitro models demonstrated that long-chain fatty acids upregulated ACE2 expression in primary human hepatocytes.
The findings presented in this study shed light on the complex relationship between the expression of Angiotensin-converting enzyme 2 (ACE2), chronic fibroinflammatory liver diseases, and their association with metabolic factors. This discussion will delve into the implications of these results, their significance in the context of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, and the potential mechanistic insights they provide.
ACE2 Upregulation in Steatohepatitis and Patient Overweight
One of the key observations in this study is the upregulation of ACE2 expression in patients with steatohepatitis, particularly in those who are overweight. The study revealed that both the basal and apical poles of hepatocyte chords displayed an increased density of ACE2 receptors in individuals with steatohepatitis. This upregulation was correlated with the percentage of fat area in the liver, enhanced immune reactivity, and fibrogenesis. Moreover, in vitro experiments using primary human hepatocytes demonstrated that the exposure to long-chain fatty acids, such as oleic and stearic acids, led to increased ACE2 mRNA expression, corroborating the clinical data.
These findings suggest that the presence of steatohepatitis and a high-fat environment play a significant role in the upregulation of ACE2 receptors in liver cells. Such an upregulation appears to be a physiological response to the increased load of fatty acids in the liver, potentially serving to mitigate inflammation and promote lipid metabolism. However, the concurrent existence of elevated immune reactivity and an abundance of ACE2 receptors may create an environment conducive to viral infection, thereby amplifying inflammation and potentially leading to metabolic decompensation.
ACE2 in Liver Sinusoidal Endothelial Cells (LSECs) and Hepatocytes
The study also identified the presence of ACE2 in CLEC4M+ sinusoidal endothelial cells and CD34+ portal capillaries within steatohepatitis-affected livers. CLEC4M, known for capturing viruses, may facilitate the transfer of viruses from the sinusoidal endothelium to ACE2-positive cells, potentially contributing to viral infection in the liver. Furthermore, the co-detection of TMPRSS2 with ACE2 in hepatocytes in steatohepatitis suggests that these cells may support viral infection through the space of Disse, a region between hepatocytes and LSECs.
These observations align with previous findings of SARS-CoV-2 detection within endothelial cells in portal veins and the presence of sinusoidal microthrombi in patients who succumbed to COVID-19. These vascular anomalies, such as occlusive thrombosis, have been associated with COVID-19 and are indicative of the virus’s impact on liver vasculature.
Comparison with Previous Findings
It’s essential to address a recent report that found no evidence of increased ACE2 expression in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). The authors of this report analyzed the GSE48452 transcriptomic microarray dataset, which is included in the larger dataset used in this study. While the GSE48452 dataset did not show significant differences between lean subjects without MASLD and other groups, our results indicate that ACE2 mRNA levels were higher in non-alcoholic steatohepatitis (NASH) compared to obese individuals without MASLD and those with simple steatosis.
Moreover, international studies that included millions of patients have identified a higher risk of COVID-19 in individuals with metabolic syndrome, including those with MASLD. This risk is particularly pronounced in NASH and NAFLD patients, suggesting a significant connection between metabolic-associated liver diseases and COVID-19 susceptibility.
The Role of Fatty Acids, Inflammation, and Interferon Response
The upregulation of ACE2 in response to an excess of fatty acids may serve as a protective mechanism for hepatocytes against inflammation and promote fatty acid oxidation through the Angiotensin 1-7/Mas axis. This regulatory loop, while potentially beneficial for the liver under normal circumstances, may have been exploited by SARS-CoV-2 during its evolution, rendering individuals with fatty liver diseases more susceptible to infection.
The findings also suggest that the balance between innate immune reactivity and the availability of ACE2 receptors in the context of fatty liver diseases plays a critical role in promoting viral infection. The endocytosis of virus-receptor complexes, rapid depletion of cell surface ACE2, and subsequent metabolic decompensation and amplified inflammation may contribute to the increased severity of COVID-19 in individuals with MASLD.
In conclusion, the relationship between MASLD and COVID-19 susceptibility appears to be multifaceted. The study findings suggest that individuals with MASLD may be at an increased risk of SARS-CoV-2 infection due to upregulated ACE2 expression in their liver cells, particularly in the presence of steatohepatitis. This upregulation is likely a physiological compensatory mechanism in response to the liver’s increased fatty acid load. However, it also creates an environment where viral infection and amplified inflammation are more likely to occur, potentially leading to patient decompensation.
Understanding the complex interplay between MASLD, ACE2, and viral infections like SARS-CoV-2 is crucial in improving patient care, early intervention, and treatment strategies for individuals with metabolic-associated liver conditions. Further research is needed to explore these relationships and develop targeted approaches for the management of MASLD in the context of COVID-19 and other viral infections.
reference link: https://www.sciencedirect.com/science/article/pii/S2589555923002677