The role of the complement system in non-alcoholic fatty liver disease

Nguyen, Van Dien 2024. The role of the complement system in non-alcoholic fatty liver disease. PhD Thesis, Cardiff University. Item availability restricted.

	PDF - Accepted Post-Print Version Restricted to Repository staff only until 1 October 2025 due to copyright restrictions. Download (9MB)
	PDF (Cardiff University Electronic Publication Form) - Supplemental Material Restricted to Repository staff only Download (916kB)

Abstract

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern. Despite its increasing prevalence, the precise mechanisms underlying NAFLD pathogenesis remain incompletely understood. This thesis investigated the role of complement component C3 in NAFLD pathogenesis using a multi-disciplinary approach, integrating human studies, experimental models, and advanced genomic techniques. Methods: The study employed human liver samples, C3 knockout mice, and in vitro experiments to elucidate the role of C3 in NAFLD. Human liver biopsy samples were analysed using bulk RNA sequencing and singlenucleus RNA sequencing to characterize C3 expression patterns. C3 knockout and wild-type mice were fed either a normal chow or a high-fat diet to establish a NAFLD model. Liver tissues from these mice were subjected to various analyses to assess the impact of C3 on NAFLD development. Results: We revealed a zonated expression pattern of C3 in hepatocytes, with the highest levels in periportal regions and lower expression in pericentral areas. C3 expression was upregulated in NAFLD patients’ livers and positively correlated with the severity of liver fat content. C3 upregulation was validated by using in silico, mouse, and cell model of NAFLD. C3 knockout mice were protected against diet-induced hepatic steatosis, exhibiting reduced lipid accumulation compared to wild-type controls. Mechanistically, C3 deficiency attenuated the induction of de novo lipogenesis and triglyceride synthesis pathways in the liver upon high-fat diet feeding. Furthermore, a novel interplay between C3 and the circadian clock was discovered, with C3 knockout mice displaying a reversal of the high-fat diet-induced alterations in core circadian gene expression. Conclusion: This thesis provides evidence for the central role of complement C3 in NAFLD pathogenesis. C3 appears to promote NAFLD development by regulating lipid metabolism pathways in hepatocytes and may interact with the circadian clock in the liver. These findings highlight C3 as a promising therapeutic target for NAFLD and lay the foundation for future translational studies.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	3 October 2024
Last Modified:	03 Oct 2024 12:30
URI:	https://orca.cardiff.ac.uk/id/eprint/172508

Actions (repository staff only)

Edit Item