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Squeezing lipids: NMR characterization of lipoprotein particles under pressure.

ABSTRACT: Determining the particle size and number of lipoprotein components found in blood plasma (HDL, LDL and VLDL) has become an important clinical tool in diagnosing risk of cardiovascular disease. Proton (¹H) NMR spectroscopy methods to quantify lipoprotein particle subclasses have been advancing since NMR lineshape analysis of plasma samples was first proposed in the 1990's. NMR methods, including a more recent DOSY-based diffusion spectroscopy test, provide the foundation for the advanced lipoprotein tests, including Lipoprotein® and Liposcale® analyses available for clinical use to determine particle size and number. At the time of this submission, no NMR studies exist which explore physical parameters of individual lipoprotein fractions when they are deformed by pressure. This study reports ¹H NMR frequency shifts and T₂* measurements for the broad methyl peak attributed to terminal methyls (cholesteryl positions 26, 27 and terminal acyl methyl groups) in three primary lipoprotein fractions as a function of hydraulic pressure. This terminal CH₃ resonance shifted linearly upfield as a function of pressure for HDL and VLDL (observed slopes of -0.014 Hz/bar). The LDL terminal CH₃ resonance shows segmented behavior, with a shallow slope between 0-900 bar (-0.008 hz/bar) and a slope similar to HDL and VDL across the range from 1000 to 2400 bar (slope -0.016 Hz/bar). ¹H T₂* values measured for VLDL and HDL dropped linearly with increasing pressure. ¹H T₂* values for LDL demonstrated segmented behavior as a function of pressure. The unique behavior observed for LDL terminal CH₃ frequency and ¹H T₂* trends suggests an approximate pressure at which phase transition occurs.

SUBMITTER: Starich MR

PROVIDER: S-EPMC7232691 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: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. 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. Methods:From 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. Results:Of 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. Conclusions:The 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.

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Squeezing lipids: NMR characterization of lipoprotein particles under pressure.

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