Angiotensin-converting enzyme 2 and hepatic SARS-CoV-2 infection: Regulation, association, and therapeutic implications

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells via the angiotensin-converting enzyme 2 (ACE2) receptor. Mounting evidence has indicated the presence of hepatic SARS-CoV-2 infection and liver injury in patients with coronavirus disease 2019 (COVID-19). Understanding the mechanisms of hepatic SARS-CoV-2 infection is crucial for addressing COVID-19–related liver pathology and developing targeted therapies. This editorial discusses the significance of ACE2 in hepatic SARS-CoV-2 infection, drawing on the research by Jacobs et al. Their findings indicate that hepatic ACE2 expression, frequency of hepatic SARS-CoV-2 infection, and severity of liver injury are elevated in patients with pre-existing chronic liver diseases. These data suggest that hepatic ACE2 could be a promising therapeutic target for COVID-19.

Key Words: Hepatic angiotensin-converting enzyme 2; SARS-CoV-2; Liver infection; Chronic liver diseases; COVID-19 treatment

Core Tip: Angiotensin-converting enzyme 2 (ACE2) serves as the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Jacobs et al discovered that elevated hepatic ACE2 expression during metabolic dysfunction may facilitate SARS-CoV-2 infection, which could potentially exacerbate the severity of coronavirus disease 2019 (COVID-19), suggesting ACE2 as a promising therapeutic target for COVID-19.

INTRODUCTION

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is an enveloped virus with a positive-sense, single-stranded RNA genome[1]. It encodes several structural proteins, including the spike, nucleocapsid, envelope, and membrane proteins[2,3]. The receptor-binding domain (RBD) within the subunit 1 domain of spike plays a key role in viral entry by binding to the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell surface. Membrane proteases, including transmembrane protease serine 2 and furin, cleave the spike protein, enabling viral-host cell fusion[2-5].

Discovered in 2000, ACE2 is a homologue of ACE and functions as a peptidase that catalyzes the cleavage of angiotensin (Ang). ACE2 primarily converts Ang I and Ang II into Ang 1-9 (with nine non-functional amino acids). ACE2 counteracts ACE, which converts Ang I into Ang II, a molecule that induces vasoconstriction and increases blood pressure. Therefore, ACE2 can regulate vasoconstriction and electrolyte and fluid balance[6-8]. Moreover, ACE2 suppresses liver lipogenesis, enhances fatty acid oxidation, and inhibits gluconeogenesis, thereby alleviating inflammation and ameliorating metabolic dysfunction-associated steatotic liver disease (MASLD)[9-12].

In 2003, ACE2 was identified as the primary receptor for the SARS-CoV that facilitated viral entry by binding to spike[13]. The receptor function of ACE2 can interfere with its enzymatic activity[14,15]. ACE2 has since been identified as a cellular receptor for several coronaviruses, including SARS-CoV, SARS-CoV-2, HCoV-NL63, HCoV-OC43, and HCoV-HKU1 in humans and MERS-CoV-like viruses NeoCoV and PDF-2180 in bats[2,16,17].

Recent evidence, including research by Jacobs et al[18], has emphasized the substantial role of ACE2 in hepatic SARS-CoV-2 infection[15,18-20]. In this editorial, we discuss the pathophysiology of hepatic SARS-CoV-2 infection, explore its association with pre-existing chronic liver diseases and ACE2 regulation, and consider the potential of ACE2-targeted therapies for treating COVID-19.

SARS-COV-2 INFECTION IN THE LIVER

Accumulating evidence has indicated that in addition to the respiratory system, SARS-CoV-2 can also affect the cardiovascular system, digestive tract, and biliary system[21,22]. Liver injury is common in patients with COVID-19, occurring in approximately 15%–65% of cases[23-28]. The most frequent liver-related manifestations post-SARS-CoV-2 infection include elevated levels of alanine amino transferase, aspartate aminotransferase, and gamma-glutamyl transferase[26,29-31]. Histopathological analysis showed the presence of portal venous and sinusoidal microthrombi, microvesicular and macrovesicular steatosis, mild portal inflammation, portal fibrosis, and inflammation characterized by lymphocytic infiltration[19,28]. SARS-CoV-2–induced cellular alterations include apoptosis, binuclear hepatocytes, mitochondrial swelling, endoplasmic reticulum dilatation, and decreased glycogen granules[19]. SARS-CoV-2–induced liver injury has molecular signatures similar to hepatitis B and C, including activation of interferon and JAK-STAT signaling and deregulation of metabolism-association genes[32]. COVID-19–induced liver injury may be attributed to the direct effect of SARS-CoV-2 on hepatocytes[19,28,32,33] or may result from indirect effects including immune cell–mediated liver damage, ischemic/hypoxic damage, and antiviral drug–induced liver damage[22,34,35].

PRE-EXISTING LIVER DISEASES EXACERBATE THE SEVERITY OF COVID-19

Pre-existing liver diseases can exacerbate the severity of COVID-19. COVID-19 patients with pre-existing MASLD are at an increased risk of progression to severe forms of the disease[30,36]. Hepatic lipid droplet levels are correlated with hepatic SARS-CoV-2 infection[18,37]. Additionally, mortality rates for COVID-19 patients have increased among those with pre-existing hepatitis B/C or cirrhosis[38,39]. These findings indicate that chronic liver diseases may promote COVID-19 progression, whereas SARS-CoV-2 infection may, in turn, aggravate pre-existing liver conditions.

UPREGULATION OF ACE2 EXPRESSION IN LIVER TISSUES WITH PRE-EXISTING LIVER DISEASES

ACE2 is expressed in liver cholangiocytes, hepatocytes, and endothelial cells but not in Kupffer cells or T and B lymphocytes[9,18,28,32,40,41]. ACE2 expression levels in cholangiocytes were similar to those of type 2 alveolar cells in lungs[33].

Evidence has shown that hepatic ACE2 expression is increased in various chronic or acute liver diseases and that fat accumulation induces ACE2 expression. Hepatic ACE2 expression is upregulated in patients with nonalcoholic fatty liver and nonalcoholic steatohepatitis. Furthermore, hepatic ACE2 expression positively correlates with increased hepatic fat accumulation[18,20,37]. Other stresses, such as hepatocellular hypoxia, can also induce ACE2 expression[12]. ACE2 expression increases in the liver tissues of patients with liver fibrosis[12,28,37,42]. Upregulation of ACE2 expression may promote COVID-19 progression, as evidenced by the observation that hepatic ACE2 expression is increased in the livers of patients who died from COVID-19, aligning with the high mortality seen in COVID-19 patients with pre-existing chronic liver diseases.

TARGETING ACE2 IN COVID-19

Several antiviral medications have been approved for COVID-19 treatment, including remdesivir, molnupiravir, and nirmatrelvir-ritonavir. These medications function by inhibiting viral replication, thereby decreasing host viral loads, albeit without directly eradicating the virus. Combinatorial therapeutic approaches may improve the treatment outcomes for COVID-19[43,44]. Considering the significance of ACE2 in SARS-CoV-2 infection, targeting ACE2 may have antiviral efficacy.

Reducing ACE2 expression may prevent SARS-CoV-2 infection. Small molecule compounds targeting genes that regulate ACE2 expression (e.g., Farnesoid X receptor) or ACE2 deubiquitinating enzymes (e.g., USP2) have been explored[21,45]. Alternatively, inhibiting the binding of viral spike protein to ACE2 may prevent SARS-CoV-2infection. Strategies to block virus–ACE2 interactions include anti-spike protein antibodies, anti-ACE2 monoclonal antibodies, soluble ACE2 extracellular domains, and oligonucleotide aptamers that specifically target the RBD of the spike protein[46-50]. Moreover, enhancing the enzymatic activity of ACE2 to inhibit viral binding using drugs such as imatinib and methazolamide could also serve as a viable therapeutic approach[15].

However, SARS-CoV-2 may hijack ACE2, suppressing its normal physiological functions and potentially worsening pre-existing liver diseases[14,15]. Therefore, understanding whether these strategies targeting ACE2 have serious side effects requires further investigation.

CONCLUSION

SARS-CoV-2 infects the liver by binding to ACE2, whose expression is upregulated in the liver tissues of patients with pre-existing liver diseases. Therefore, blocking the viral entry receptor ACE2 may have potential for preventing hepatic SARS-CoV-2 infection. However, given that targeting ACE2 may disturb its normal physiological function, further studies should be conducted to investigate the efficacy and the side effect of strategies targeting ACE2.