Targeting C3 to treat fatty liver disease

Iliescu, Adrian 2026. Targeting C3 to treat fatty liver disease. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MASLD) is characterised by excess hepatic fat accumulation and is becoming a major health problem due to the rise in obesity rates. There are no approved treatments in the UK, and the disease costs the NHS in excess of £17 billion annually. The complement system is a key player in inflammation and innate immunity. It was shown to impact lipid transport around the body. This study explored the role of complement component 3 (C3) in the pathogenesis of MASLD. METHODS: In vitro, human hepatocyte cell lines (IHH and Huh7) were exposed to free fatty acids. C3 function was assessed using Western blotting, qPCR, Oil Red O, H&E, Picrosirius staining, and immunofluorescence. Pharmacological inhibition of complement activation used Compstatin and Danicopan. In vivo, C3 deficient and wildtype mice were fed a choline-deficient, amino acid-defined, high-fat diet (CDAHFD) for 14 weeks. Bulk RNA sequencing was used to define global transcriptional changes associated with diet and C3 deficiency. RESULTS: Lipid exposure increased hepatic C3 expression and induced complement factor D, indicating coordinated activation of complement signalling during lipid stress. Inhibition of C3 or upstream complement activation reduced lipid accumulation in vitro. In vivo, C3 deficiency reduced hepatic steatosis but increased fibrosis. Complement receptors including C3ar1, C5ar1, and C5ar2 were upregulated in C3-deficient livers. Transcriptomic analysis revealed activation of lipid metabolism, inflammatory, fibrogenic, and complement-related pathways in response to dietary challenge, with distinct modulation by C3 status. CONCLUSION: These findings identify C3 as a key regulator of hepatic lipid handling and disease progression in MASLD. While C3 promotes steatosis, its deficiency alters immune-metabolic signalling and is associated with increased fibrotic remodelling, indicating a complex, stage-dependent role in disease progression. C3 therefore represents a potential therapeutic target, although strategies will need to consider its dual metabolic and immunological functions.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	24 September 2026
Last Modified:	24 Sep 2026 11:06
URI:	https://orca.cardiff.ac.uk/id/eprint/189750

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