Studies on the anti-atherogenic and anti-steatotic actions of Urolithin C

Albalawi, Faizah 2025. Studies on the anti-atherogenic and anti-steatotic actions of Urolithin C. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Abstract Background: Atherosclerosis, the major cause of cardiovascular diseases (CVDs), is a chronic inflammatory condition that contributes significantly to global morbidity and mortality. Current pharmacological strategies targeting hyperlipidaemia, such as statins, are associated with considerable residual risk for CVDs together with various side effects. Consequently, alternative avenues need to be sought. Nutraceuticals, such as urolithins (A, B, C, and D), have been highlighted as potential candidates affecting multiple atherogenic risk factors and with a favourable safety profile for the prevention and treatment of atherosclerosis. Previous studies in the host laboratory found urolithin A (UA) to exert various anti-inflammatory and anti-atherogenic effects on different types of cells in vitro and in male LDL receptor-deficient mice (LDLr-/-) fed a high-fat diet (HFD) in vivo. This study focused on the investigation of the effects of urolithin C (UC) on atherosclerosis development and progression in male LDLr-/- mice together with the underlying molecular mechanisms. Methods: Male LDLr-/- mice (8 weeks old) were fed high-fat diet (HFD) with or without UC supplementation (50 mg/kg/day) for 12 weeks to induce atherosclerosis. Comprehensive assessments included organ weight measurements, peripheral blood immunophenotyping, plasma lipid profiling, and quantification of atherosclerotic plaque burden, inflammation and stability. To investigate UC's effects on non-alcoholic fatty liver disease (NAFLD), which is frequently linked to atherosclerosis, liver sections underwent histological analysis for cellularity, morphology, and hepatic steatosis assessment. Additionally, an in vitro NAFLD model using HepG2 hepatocytes was established to examine UC's effects on reactive oxygen species (ROS) levels and lipid accumulation. RNA sequencing was also utilised to evaluate alterations in gene expression in the thoracic aorta, liver tissue and HepG2 cells. Results: Male LDLr-/- mice receiving HFD supplemented with UC for 12 weeks showed improved plasma lipid profiles, attenuation of plaque inflammation, and enhanced plaque stability. Liver analysis revealed decreased steatosis and improved morphology, while in vitro NAFLD modeling confirmed UC’s ability to reduce lipid accumulation and oxidative stress in HepG2 cells. RNA sequencing of aorta, liver, and HepG2 cells demonstrated that UC upregulated antioxidant and anti-inflammatory pathways (including NRF2, IL-10, IL-4/IL-13), activated protective regulators such as STAT3, improved mitochondrial efficiency and fatty acid β-oxidation, and modulated lipid metabolism by promoting plasma lipoprotein assembly and reverse cholesterol transport. Additionally, UC suppressed pro-inflammatory signaling pathways (NF-κB, STAT3, T cell signaling), downregulated genes linked to mitochondrial dysfunction and inflammation (e.g., Map4k4), and enhanced expression of protective genes XII (Hint2, Sirt3, Foxa2), collectively supporting its therapeutic effects against atherosclerosis and NAFLD. Conclusions: The results of this study provide valuable insights into the anti-atherogenic actions of UC and implicate it as a potential nutraceutical candidate for preventing and managing atherosclerotic CVDs worldwide. This is possibly achievable because of its lack of adverse side effects and the comparatively low cost compared to standard pharmacological medications. Further exploration of the potential of UC should be conducted through extensive clinical trials.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	5 February 2026
Last Modified:	05 Feb 2026 15:50
URI:	https://orca.cardiff.ac.uk/id/eprint/184471

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