Hepatic steatosis opens the doors of the liver to the virus · Inserm, science for health

The liver is a particularly vulnerable organ in the event of Covid-19 disease. At the Institute of Nutrition, Metabolism and Cancer in Rennes, Orlando Musso and his team have just shown that hepatic steatosis, a disease characterized by an accumulation of fats in liver cells, promotes the availability of receptors that transmit the SARS coronavirus to CoV- 2 pass on enter. However, around one billion people worldwide are affected by fatty liver disease.

Why is liver disease a risk factor for severe Covid-19 disease? Why does infection cause liver complications in some patients? The researcher is fascinated by the close connections between Covid-19 and liver diseases Insert Orlando Musso and his team from the Institute of Nutrition, Metabolism and Cancer in Rennes. Since the pandemic, these researchers have been studying the biological mechanisms involved in these relationships with the aim of shedding light on the susceptibility to infection by the SARS-CoV-2 coronavirus depending on the health status of this organ. The team was particularly interested in fatty liver disease because the disease is very widespread: it is estimated to affect between 25 and 45% of the adult population, depending on the region of the world. In France, around one in five adults is affected. This disease is often associated with excessive calorie intake and obesity and leads to an inflammatory state of the liver that impairs its function.

Orlando Musso and his colleagues have just shown that the unusually high amount of fats in these patients’ liver cells increases the amount of angiotensin II converting enzyme (ACE2) on the surface of these cells. However, this enzyme, which is normally involved in regulating blood pressure, is also the receptor through which SARS-CoV-2 infects them.

Clinical cases and cultures in vitro

As part of this work, researchers examined liver tissue samples from surgeries performed on patients with liver disease who did not have SARS-CoV-2 infection to clearly distinguish what alone constitutes liver disease. They quantified the expression of the gene that leads to the synthesis of ACE2 in the liver cells of 243 patients, including 126 with fatty liver disease. They then validated their results in a cohort of 161 additional cases who presented with inflammatory liver disease without a diagnosis of fatty liver disease. Finally, they searched for and localized the ACE2 protein in the livers of 16 patients. All of this work allowed them to show a link between liver steatosis and high ACE2 expression in the liver.

“ In patients with fatty liver disease, ACE2 levels increase with increasing age, liver fat content and intensity of inflammation. In patients with inflammatory liver disease without a diagnosis of fatty liver disease, ACE2 expression is increased only if these individuals are overweightexplains Orlando Musso. ACE2 is found on the surface of hepatocytes, the liver cells that ensure their metabolic functions Endothelial cells which line the inside of the organ’s blood vessels. This result is important because endothelial cells represent an exchange platform between hepatocytes and the bloodstream, which could facilitate the transition of the virus from the blood into hepatocytes. » These clinical observations have been confirmed by experiments in vitro and the team was able to demonstrate that the unusually high accumulation of certain fatty acids induces gene expression in cultured human hepatocytes ACE2.

Controlling ACE2 expression

Given this new data: “ One can imagine that the excessive presence of the ACE2 protein on the surface of liver cells could facilitate the entry of SARS-CoV-2 into the liver and that the pro-inflammatory state generated by hepatic steatosis worsens the response to infections and promotes the occurrence of functional disorders », explains the researcher. In addition to providing new fundamental insights, this work confirms the potential interest in strategies that would allow controlling the expression of ACE2 on the surface of cells to reduce susceptibility to severe forms of Covid-19. “ A human study has previously shown that pharmacological control of ACE2 expression reduces the risk of SARS-CoV-2 infection, including in the liver. », Indicates the researcher. Over and beyond, ” These new data highlight the importance of protecting potentially vulnerable patients through booster vaccinations and better food hygiene », he emphasizes in conclusion.

Orlando Musso is a researcher on the team Exogenous and endogenous stress, plasticity of reactions and pathologies