COVID-19 News: Fatty Acids Impact ACE2 Receptor Expression In Metabolic Dysfunction-Associated Steatotic Liver Disease

COVID-19 News: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), formerly known as Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH), is a prevalent condition affecting approximately 25% of the global population. This multifaceted liver disorder encompasses a spectrum of pathological changes, including steatosis (accumulation of fat in the liver), inflammation, fibrosis, and the development of pre-neoplastic foci. As the world grapples with the ongoing COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), there has been a growing concern regarding the vulnerability of individuals with MASLD to this deadly disease. Recent studies have indicated that patients with fatty liver disease are at a higher risk of experiencing severe COVID-19 and liver injury. One key factor contributing to this vulnerability is the presence of a cell surface protein known as Angiotensin-converting enzyme 2 (ACE2), which serves as the primary receptor for SARS-CoV-2.


                                                                                    Graphical Abstract
 
In this COVID-19 News report, we explore the expression levels and cellular sources of ACE2 and its co-receptors in MASLD and other fibroinflammatory liver diseases. We will delve into the implications of these findings for the management and treatment of patients with fatty liver disease, especially in the context of the ongoing COVID-19 pandemic.
 
The Role of ACE2 in SARS-CoV-2 Infection
SARS-CoV-2 is a member of the coronavirus family, and its cell entry depends on the binding of the viral spike protein to a specific receptor, ACE2. This interaction allows the virus to enter host cells, where it can replicate and cause infection. In addition to ACE2, SARS-CoV-2 also utilizes co-receptors such as TMPRSS2 and CLEC4M for efficient cell entry. Understanding the expression and localization of ACE2 and these co-receptors is crucial for comprehending how the virus interacts with host cells.
 
While the primary site of infection for SARS-CoV-2 is the respiratory system, the presence of viral RNA in liver tissues has raised questions about the role of the liver in COVID-19. Some studies have identified viral particles in hepatocytes, suggesting that the liver may be a target for viral infection. Therefore, investigating the expression and distribution of ACE2 and its co-receptors in the liver becomes imperative, especially in the context of MASLD.
 
ACE2 and Its Role in Liver Physiology
ACE2 is a multifunctional enzyme that plays a critical role in the regulation of the renin-angiotensin-aldosterone system (RAAS). This system is responsible for c ontrolling blood pressure and maintaining fluid and electrolyte balance. ACE2 cleaves angiotensin II (Ang II) into Ang1-7, which activates the MAS1 receptor, leading to smooth muscle relaxation, hypotension, and cardioprotection. In addition to its role in the RAAS, ACE2 also cleaves other substrates, including inflammatory peptides and molecules involved in glucose metabolism.
 
Studies have shown that activation of the ACE2/Ang1-7/MAS axis can downregulate hepatic lipid uptake and lipogenesis while favoring lipid oxidation and improving glucose metabolism. This mechanism is particularly relevant in the context of NAFLD and NASH, as these conditions are characterized by an imbalance in lipid metabolism, oxidative stress, inflammation, and liver fibrosis.
 
Expression and Cellular Sources of ACE2 in Fatty Liver Disease
The expression and localization of ACE2 in the liver, especially in the context of fatty liver diseases, have been the focus of extensive research. Studies have shown that ACE2 is detected in various liver cell types, including hepatocytes, liver sinusoidal endothelial cells (LSECs), bile canaliculi, cholangiocytes, and capillary vessels. This widespread presence of ACE2 suggests that multiple cell types in the liver may be susceptible to SARS-CoV-2 infection.
 
One key finding from this research is the upregulation of ACE2 expression in patients with fatty liver disease, particularly in those with steatohepatitis (inflammation of the liver associated with fat accumulation). This upregulation of ACE2 is not only associated with age but also correlates with liver fat content, inflammation, increased immune reactivity, and fibrogenesis. These findings indicate that individuals with fatty liver disease, especially those with steatohepatitis, have an increased availability of ACE2 receptors in their livers.

Furthermore, ACE2 was found to be upregulated in a context of patient overweight. This suggests that there is a link between metabolic factors and ACE2 expression in the liver. It is worth noting that ACE2 expression was not significantly altered in patients with alcoholic or viral hepatitis, indicating that this upregulation is specific to fatty liver disease.
 
Experimental Evidence: ACE2 Regulation by Fatty Acids
To better understand the mechanisms underlying ACE2 upregulation in fatty liver disease, researchers conducted experiments using primary human hepatocytes in vitro. The findings revealed that long-chain fatty acids, such as oleic and stearic acids, could induce ACE2 mRNA expression. This result reinforces the hypothesis that the excess of fatty acids, which is characteristic of fatty liver disease, plays a crucial role in the upregulation of ACE2 expression.
 
In contrast, treatment with inflammatory cytokines alone did not lead to an increase in ACE2 mRNA expression in primary human hepatocytes. This suggests that the mechanism of ACE2 regulation in the liver is specific to fatty acids and may not be influenced by inflammation alone.
 
Implications for Clinical Practice and Further Research
Understanding the cellular sources of ACE2 in the liver and the factors that influence its availability is of utmost importance, especially in the context of the COVID-19 pandemic. The findings from this research have several important implications:
 
-Increased Vulnerability to COVID-19: Patients with fatty liver disease, particularly those with steatohepatitis, may be at higher risk for severe COVID-19 and liver injury due to the increased availability of ACE2 receptors. This knowledge is critical for healthcare providers, as it helps identify a vulnerable population that may require special attention, including timely vaccination boosters.
 
-Dietary Adjustments: The link between long-chain fatty acids and ACE2 upregulation suggests that dietary adjustments may be a valuable approach in managing fatty liver disease. Controlling the intake of specific fatty acids may help mitigate the risk of severe COVID-19 and liver complications in these patients.
 
-Hygiene Practices: Patients with fatty liver disease may benefit from stricter hygiene practices and protective measures to reduce the risk of SARS-CoV-2 exposure. Given the prevalence of ACE2 in various liver cell types, avoiding potential sources of infection becomes crucial.
 
-Further Research: This study opens the door to further research on the complex interplay between fatty liver disease, ACE2 expression, and viral infection. Investigating the underlying molecular mechanisms could reveal novel therapeutic targets for both COVID-19 and fatty liver disease.
 
Conclusion
The research presented in this article sheds light on the intricate relationship between fatty liver disease and the expression of the SARS-CoV-2 receptor ACE2. Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are shown to have increased ACE2 expression, particularly in the presence of steatohepatitis and in overweight individuals. Furthermore, experiments with primary human hepatocytes in vitro demonstrate that long-chain fatty acids induce ACE2 expression.
 
These findings have important implications for the management of patients with fatty liver disease, as they may be at higher risk of severe COVID-19 and liver injury. Recognizing the link between fatty acids and ACE2 upregulation suggests potential strategies for risk reduction, including dietary modifications and enhanced hygiene practices.
 
In conclusion, this research contributes to our understanding of the interactions between metabolic disorders and viral infection, offering valuable insights for healthcare providers and researchers as they work to protect vulnerable patients and develop effective treatment strategies. Further studies are needed to explore the underlying molecular mechanisms and potential therapeutic interventions related to ACE2 in the context of fatty liver disease and COVID-19.
 
The study findings were published in a peer reviewed journal: JHEP Reports.
https://www.sciencedirect.com/science/article/pii/S2589555923002677
 
For the latest COVID-19 News, keep on logging to Thailand Medical News.