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Lipoprotein lipidomics in obesity-associated metabolic and hepatic disorders



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Over the last few decades, obesity has reached epidemic proportions. Obesity is strongly associated with insulin resistance (IR), hyperglycaemia, mixed dyslipidaemia, and hypertension. These metabolic risk factors, grouped under the definition of the Metabolic Syndrome (MetS), increase the risk of cardiovascular disease (CVD). Non-alcoholic fatty liver disease (NAFLD) is one of the most common co-morbidities of MetS. NAFLD ranges from simple steatosis to more aggressive forms, with the potential to evolve to hepatocellular carcinoma and CVD. Lipoprotein dysmetabolism is crucial to both MetS and NAFLD and few studies have investigated the circulating lipidome, defined as the complete lipid profile in a specific tissue/biofluid, in these conditions. The work contained in this thesis studied the lipoprotein remodelling occurring in two cohorts; MetS cohort including 11 healthy people and 14 MetS subjects and BioNASH cohort including 20 healthy people and 89 biopsy-proven patients across the entire spectrum of NAFLD. To this end, we employed state-of-the-art analytical techniques (mass spectrometry-based) along with molecular biology assays to study the serum and lipoprotein lipidome of these patients. In the MetS study, we found that the circulating lipidome of MetS was characterised by a phospholipid (PL) dysmetabolism. The latter was driven, at least in part, by a reduced activity of the enzyme lecithin–cholesterol acyltransferase (LCAT). Dysfunctional LCAT could partly mediate the elevated CVD risk in MetS patients. Our study demonstrated, for the first time, the link between reduced LCAT activity and plasma lipidome in MetS. In the BioNASH cohort, we observed a generalised PL and polyunsaturated fatty acids (PUFA) depletion in NAFLD compared to the control group. By using fast protein liquid chromatography, we isolated HDL and VLDL fractions where we performed lipidomic analyses. As opposed to VLDL, the HDL lipidome was characterised by PL and PUFA depletion. These changes have been reported in hepatic lipidomic studies of NAFLD patients, thus suggesting a close link between peripheral tissues and the liver via HDL. These results provide the basis for the study of HDL composition as a novel player in the pathogenesis of NAFLD. In conclusion, these data demonstrate how the study of lipoprotein metabolism in obesity-related metabolic disorders can shed light on novel pathophysiological mechanisms. Further efforts along these lines will clarify the role of LCAT in MetS and CVD alongside establishing the contribution of the HDL lipidome to the liver composition of NAFLD patients.





Griffin, Julian
Vacca, Michele


Obesity, lipoprotein metabolism, LC-MS, lipidomics


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge