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Abstract
BackgroundMetabolic diseases such as obesity and diabetes are associated with changes in high-density lipoprotein (HDL) particles, including changes in particle size and protein composition, often resulting in abnormal function. Recent studies suggested that patients with non-alcoholic fatty liver disease (NAFLD), including individuals with non-alcoholic steatohepatitis (NASH), have smaller HDL particles when compared to individuals without liver pathologies. However, no studies have investigated potential changes in HDL particle protein composition in patients with NAFLD, in addition to changes related to obesity, to explore putative functional changes of HDL which may increase the risk of cardiovascular complications.MethodsFrom a cohort of morbidly obese females who were diagnosed with simple steatosis (SS), NASH, or normal liver histology, we selected five matched individuals from each condition for a preliminary pilot HDL proteome analysis. HDL particles were enriched using size-exclusion chromatography, and the proteome of the resulting fraction was analyzed by liquid chromatography tandem mass spectrometry. Differences in the proteomes between the three conditions (normal, SS, NASH) were assessed using label-free quantitative analysis. Gene ontology term analysis was performed to assess the potential impact of proteomic changes on specific functions of HDL particles.ResultsOf the 95 proteins identified, 12 proteins showed nominally significant differences between the three conditions. Gene ontology term analysis revealed that severity of the liver pathology may significantly impact the anti-thrombotic functions of HDL particles, as suggested by changes in the abundance of HDL-associated proteins such as antithrombin III and plasminogen.ConclusionsThe pilot data from this study suggest that changes in the HDL proteome may impact the functionality of HDL particles in NAFLD and NASH patients. These proteome changes may alter cardio-protective properties of HDL, potentially contributing to the increased cardiovascular disease risk in affected individuals. Further validation of these protein changes by orthogonal approaches is key to confirming the role of alterations in the HDL proteome in NAFLD and NASH. This will help elucidate the mechanistic effects of the altered HDL proteome on cardioprotective properties of HDL particles.
Highlights
Metabolic diseases such as obesity and diabetes are associated with changes in high-density lipoprotein (HDL) particles, including changes in particle size and protein composition, often resulting in abnormal function
Our study focused on a group of 15 morbidly obese females for an exploratory HDL proteomics analysis, 5 with no abnormal liver histology, 5 with SS and 5 with nonalcoholic steatohepatitis (NASH)
Our analysis revealed no correlation of protein abundance with HDL particle size, suggesting that the particle size reduction in non-alcoholic fatty liver disease (NAFLD) is likely mediated by changes in lipid composition
Summary
Metabolic diseases such as obesity and diabetes are associated with changes in high-density lipoprotein (HDL) particles, including changes in particle size and protein composition, often resulting in abnormal function. No studies have investigated potential changes in HDL particle protein composition in patients with NAFLD, in addition to changes related to obesity, to explore putative functional changes of HDL which may increase the risk of cardiovascular complications. Metabolic disorders in humans, such as obesity or diabetes, are often associated with liver abnormalities, Rao et al Clin Proteom (2018) 15:10 cardiovascular disease (CVD), potentially mediated by obesity, elevated plasma triglyceride and low density lipoprotein (LDL) cholesterol levels, and altered high-density lipoprotein (HDL) cholesterol levels, reflecting an overall atherogenic lipid profile [2]. In obese and diabetic individuals, plasma levels of HDL-C are often reduced, with a preponderance of small, dense HDL particles. This is further exacerbated in patients with NAFLD and NASH [4]. It has been proposed that these particles are dysfunctional increasing the risk for atherosclerosis [5]
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