Abstract
Background: Lipoprotein particles with abnormal compositions, such as lipoprotein X (LP-X) and lipoprotein Z (LP-Z), have been described in cases of obstructive jaundice and cholestasis. The study objectives were to: (1) develop an NMR-based assay for quantification of plasma/serum LP-Z particles, (2) evaluate the assay performance, (3) isolate LP-Z particles and characterize them by lipidomic and proteomic analysis, and (4) quantify LP-Z in subjects with various liver diseases. Methods: Assay performance was assessed for linearity, sensitivity, and precision. Mass spectroscopy was used to characterize the protein and lipid content of isolated LP-Z particles. Results: The assay showed good linearity and precision (2.5–6.3%). Lipid analyses revealed that LP-Z particles exhibit lower cholesteryl esters and higher free cholesterol, bile acids, acylcarnitines, diacylglycerides, dihexosylceramides, lysophosphatidylcholines, phosphatidylcholines, triacylglycerides, and fatty acids than low-density lipoprotein (LDL) particles. A proteomic analysis revealed that LP-Z have one copy of apolipoprotein B per particle such as LDL, but less apolipoprotein (apo)A-I, apoC3, apoA-IV and apoC2 and more complement C3. LP-Z were not detected in healthy volunteers or subjects with primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, or type 2 diabetes. LP-Z were detected in some, but not all, subjects with hypertriglyceridemia, and were high in some subjects with alcoholic liver disease. Conclusions: LP-Z differ significantly in their lipid and protein content from LDL. Further studies are needed to fully understand the pathophysiological reason for the enhanced presence of LP-Z particles in patients with cholestasis and alcoholic liver disease.
Highlights
In the past two decades, nuclear magnetic resonance spectroscopy (NMR) has become a powerful tool to measure lipoprotein particle concentrations [1]
Accurate quantitation of lipoprotein classes and subclasses can be accomplished by NMR for three reasons: (1) each class of lipoproteins, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), emits an NMR signal with a unique lineshape enabling their distinction from one another, (2) the amplitudes of these unique NMR signals are directly proportional to the number of particles emitting the signal thereby allowing for accurate quantification, and (3) there is a magnetic property specific to lipoproteins that causes the lipids in larger particles to emit signals that are characteristically different in shape and higher in frequency from signals emitted by lipids in smaller particles [1,2,3]
lipoprotein Y (LP-Y) particles are formed by deficiencies in lecithin-cholesterol acyltransferase (LCAT) and hepatic lipase (HL) activities and may be an intermediate-density lipoprotein (IDL) or a VLDL remnant [7,14,15]
Summary
In the past two decades, nuclear magnetic resonance spectroscopy (NMR) has become a powerful tool to measure lipoprotein particle concentrations [1]. It has been hypothesized that additional, unaccounted for signals may come from lipoproteins with different lipid compositions that are not captured by the existing algorithms This offers an opportunity to identify novel lipoprotein species in human samples. Patients with late-stage cholestatic liver diseases are known to have a distinct pattern of dyslipidemia in which circulating lipoproteins have abnormal compositions, electrophoretic mobility, and appearance [7]. One of these lipoproteins, called lipoprotein X (LP-X), has a multilamellar structure that is enriched in phospholipids and free cholesterol (FC) [8,9,10,11]. Further studies are needed to fully understand the pathophysiological reason for the enhanced presence of LP-Z particles in patients with cholestasis and alcoholic liver disease
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