Hepatic angiotensin-converting enzyme 2 expression in metabolic dysfunction-associated steatotic liver disease and in patients with fatal COVID-19.

Autor:	Jacobs AK; Hepatology Laboratory, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom. angus.jacobs@ed.ac.uk., Morley SD; Hepatology Laboratory, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom., Samuel K; Scottish National Blood Transfusion Service, Jack Copland Centre, Edinburgh EH14 4BE, United Kingdom., Morgan K; Hepatology Laboratory, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom., Boswell L; Institute for Regeneration and Repair, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom., Kendall TJ; Institute for Regeneration and Repair, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom.; Edinburgh Pathology, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom., Dorward DA; Edinburgh Pathology, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom., Fallowfield JA; Institute for Regeneration and Repair, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom., Hayes PC; Hepatology Laboratory, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom., Plevris JN; Hepatology Laboratory, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
Jazyk:	angličtina
Zdroj:	World journal of gastroenterology [World J Gastroenterol] 2024 Aug 21; Vol. 30 (31), pp. 3705-3716.
DOI:	10.3748/wjg.v30.i31.3705
Abstrakt:	Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), characterised by hepatic lipid accumulation, causes inflammation and oxidative stress accompanied by cell damage and fibrosis. Liver injury (LI) is also frequently reported in patients hospitalised with coronavirus disease 2019 (COVID-19), while pre-existing MASLD increases the risk of LI and the development of COVID-19-associated cholangiopathy. Mechanisms of injury at the cellular level remain unclear, but it may be significant that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes COVID-19, uses angiotensin-converting expression enzyme 2 (ACE2), a key regulator of the 'anti-inflammatory' arm of the renin-angiotensin system, for viral attachment and host cell invasion. Aim: To determine if hepatic ACE2 levels are altered during progression of MASLD and in patients who died with severe COVID-19. Methods: ACE2 protein levels and localisation, and histological fibrosis and lipid droplet accumulation as markers of MASLD were determined in formalin-fixed liver tissue sections across the MASLD pathological spectrum (isolated hepatocellular steatosis, metabolic dysfunction-associated steatohepatitis (MASH) +/- fibrosis, end-stage cirrhosis) and in post-mortem tissues from patients who had died with severe COVID-19, using ACE2 immunohistochemistry and haematoxylin and eosin and picrosirius red staining of total collagen and lipid droplet areas, followed by quantification using machine learning-based image pixel classifiers. Results: ACE2 staining is primarily intracellular and concentrated in the cytoplasm of centrilobular hepatocytes and apical membranes of bile duct cholangiocytes. Strikingly, ACE2 protein levels are elevated in non-fibrotic MASH compared to healthy controls but not in the progression to MASH with fibrosis and in cirrhosis. ACE2 protein levels and histological fibrosis are not associated, but ACE2 and liver lipid droplet content are significantly correlated across the MASLD spectrum. Hepatic ACE2 levels are also increased in COVID-19 patients, especially those showing evidence of LI, but are not correlated with the presence of SARS-CoV-2 virus in the liver. However, there is a clear association between the hepatic lipid droplet content and the presence of the virus, suggesting a possible functional link. Conclusion: Hepatic ACE2 levels were elevated in nonfibrotic MASH and COVID-19 patients with LI, while lipid accumulation may promote intra-hepatic SARS-CoV-2 replication, accelerating MASLD progression and COVID-19-mediated liver damage. Competing Interests: Conflict-of-interest statement: No conflict of interest has been declared by any of the authors impacting on the work presented in this manuscript. (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)
Databáze:	MEDLINE
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