Formation Of Lipoprotein Particles Research Articles

Mechanisms of Semen Cassiae to Treat Hypercholesterolemia Based on Molecular Docking

Hypercholesterolemia is a major risk factor of cardiovascular disease with high prevalence rate. Studies have shown that the traditional Chinese medicine: Semen Cassiae can reduce blood cholesterol and lipids, but the functional components and molecular mechanisms need further elucidation. In this study, molecular docking technology is used to explore the mechanism of Semen Cassiae in the treatment of hypercholesterolemia. A total 88 active ingredients and 196 isomers of Semen Cassiae were obtained from the traditional Chinese medicine database: HERB. 6 hypercholesterolemia-related drug targets: proprotein convertase subtilisin/kexin type 9 (PCSK9), thyroid Hormone Receptor β (THRB), peroxisome proliferator-activated receptors (PPARd), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), insulin receptor (IR) and squalene monooxygenase (SQLE) were obtained from the Therapeutic Target Database. After data preprocessing, molecular docking analysis was conducted using the LibDock tool in Discovery Studio software, and the main “active ingredient-target” combinations with high scores were screened. The structure results showed high binding affinity of the active ingredients to the hypercholesterolemia-related targets. Gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed the involved pathways, including cholesterol and lipid metabolism, lipoprotein particle formation, cholesterol and lipid transfer and lipoprotein particle receptor binding processes. This study revealed that the anti-hypercholesterolemia activity of Semen Cassiae is a multicomponent, multitarget, and multipathway effects, and provides evidence for further development the clinical application value of Semen Cassiae on hypercholesterolemia.

Common and Unique Transcription Signatures of YAP and TAZ in Gastric Cancer Cells

Simple SummaryYAP and TAZ are cancer-causing genes that encode proteins with similar, but not identical functions. YAP and TAZ function in diverse biological processes including cell proliferation and organ size control. Because of the high similarity in functions between YAP and TAZ, they have often been described as one entity: YAP/TAZ. However, new lines of evidence started to suggest that YAP and TAZ have unique functions as well. To understand the YAP- and TAZ-specific functions, we identified genes that are regulated solely by YAP or by TAZ. Our study revealed that YAP plays a distinct role in cell-substrate junctions, which are critical for tumour cell growth, migration, and metastasis, and both YAP and TAZ are involved in regulating blood platelets and lipid metabolism in gastric cancer cells.YAP and its paralog TAZ are the nuclear effectors of the Hippo tumour-suppressor pathway, and function as transcriptional co-activators to control gene expression in response to mechanical cues. To identify both common and unique transcriptional targets of YAP and TAZ in gastric cancer cells, we carried out RNA-sequencing analysis of overexpressed YAP or TAZ in the corresponding paralogous gene-knockouts (KOs), TAZ KO or YAP KO, respectively. Gene Ontology (GO) analysis of the YAP/TAZ-transcriptional targets revealed activation of genes involved in platelet biology and lipoprotein particle formation as targets that are common for both YAP and TAZ. However, the GO terms for cell-substrate junction were a unique function of YAP. Further, we found that YAP was indispensable for the gastric cancer cells to re-establish cell-substrate junctions on a rigid surface following prolonged culture on a soft substrate. Collectively, our study not only identifies common and unique transcriptional signatures of YAP and TAZ in gastric cancer cells but also reveals a dominant role for YAP over TAZ in the control of cell-substrate adhesion.

Exploring the effects of carrier oil type on in vitro bioavailability of β-carotene: A cell culture study of carotenoid-enriched nanoemulsions

β-carotene was encapsulated in either olive oil or flaxseed oil-in-water nanoemulsions, and it's in vitro bioaccessibility and bioavailability were determined in a simulated gastrointestinal digestion model (mouth, stomach and small intestine) combined with a Caco-2 cell monolayer model. Nanoemulsions fabricated from both types of oils significantly increased the in vitro bioaccessibility and bioavailability of β-carotene. Olive oil, however, was digested more efficiently, which generated more free fatty acids capable of forming mixed micelles. Furthermore, the mixed micelles stimulated the formation of lipoprotein particles (chylomicrons and very low-density lipoproteins), which are the transcellular carriers of β-carotene in the intestinal epithelium, leading to an increase in bioavailability. Interestingly, olive oil led to the formation of larger chylomicrons than flaxseed oil, suggesting that fatty acid type impacts the nature of the lipoprotein particles formed after lipid digestion.

Synthesis of a Fluorescent Probe for Sensing Multiple Protein States

We synthesized solvatochromic thiol‐reactive fluorescent probes 6FM‐M and 7AFM‐M possessing two‐band emission. 7AFM‐M was designed to have a smaller dipole moment than 6FM‐M and as a result it showed better separation of the two emission bands. Both probes were used to label a cysteine mutant of α‐synuclein (αSyn), a presynaptic neuronal protein associated with Parkinson's disease. We investigated the ability of the probes to sense αSyn binding to lipid membranes and αSyn fibrillization, and compared their sensitivity with that of one‐band solvatochromic probes. We found that while all the tested probes can discriminate two αSyn states, only the 7AFM‐M probe is able to clearly discriminate all three protein states of αSyn: unstructured, membrane‐bound and fibrillar αSyn. Finally, using αSyn labelled with 7AFM‐M, we demonstrated that high density of αSyn on lipid membranes may lead to the partial membrane destruction with a formation of lipoprotein particles.

Lipoprotein Particle Formation by Proapoptotic tBid

The interactions of Bcl-2 family proteins with intracellular lipids are essential for the regulation of apoptosis, a mechanism of programmed cell death that is central to the health and development of multicellular organisms. Bid and its caspase-8 cleavage product, tBid, promote the permeabilization of the mitochondrial outer membrane and sequester antiapoptotic Bcl-2 proteins to counter their cytoprotective activity. Bid and tBid also promote lipid exchange, a characteristic trait of apoptosis. Here, we show that tBid is capable of associating with phospholipids to form soluble, nanometer-sized lipoprotein particles that retain binding affinity for the antiapoptotic protein Bcl-xL. The tBid lipoprotein particles form with a lipid/protein stoichiometry in the range of 20/1 and have a diameter of ∼11.5 nm. Lipoparticle-bound tBid retains an α-helical structure and binds Bcl-xL through its third Bcl-2 homology motif, forming a soluble, lipid-associated heteroprotein complex. The results shed light on the role of lipids in mediating Bcl-2 protein mobility and interactions.

Apolipoprotein A-II induces acute-phase response associated AA amyloidosis in mice through conformational changes of plasma lipoprotein structure

During acute-phase response (APR), there is a dramatic increase in serum amyloid A (SAA) in plasma high density lipoproteins (HDL). Elevated SAA leads to reactive AA amyloidosis in animals and humans. Herein, we employed apolipoprotein A-II (ApoA-II) deficient (Apoa2−/−) and transgenic (Apoa2Tg) mice to investigate the potential roles of ApoA-II in lipoprotein particle formation and progression of AA amyloidosis during APR. AA amyloid deposition was suppressed in Apoa2−/− mice compared with wild type (WT) mice. During APR, Apoa2−/− mice exhibited significant suppression of serum SAA levels and hepatic Saa1 and Saa2 mRNA levels. Pathological investigation showed Apoa2−/− mice had less tissue damage and less inflammatory cell infiltration during APR. Total lipoproteins were markedly decreased in Apoa2−/− mice, while the ratio of HDL to low density lipoprotein (LDL) was also decreased. Both WT and Apoa2−/− mice showed increases in LDL and very large HDL during APR. SAA was distributed more widely in lipoprotein particles ranging from chylomicrons to very small HDL in Apoa2−/− mice. Our observations uncovered the critical roles of ApoA-II in inflammation, serum lipoprotein stability and AA amyloidosis morbidity, and prompt consideration of therapies for AA and other amyloidoses, whose precursor proteins are associated with circulating HDL particles.

Knockdown of FABP5 mRNA decreases cellular cholesterol levels and results in decreased apoB100 secretion and triglyceride accumulation in ARPE-19 cells

To maintain normal retinal function, retinal pigment epithelial (RPE) cells engulf photoreceptor outer segments (ROS) enriched in free fatty acids (FFAs). We have previously demonstrated fatty acid-binding protein 5 (FABP5) downregulation in the RPE/choroidal complex in a mouse model of aging and early age-related macular degeneration. FABPs are involved in intracellular transport of FFAs and their targeting to specific metabolic pathways. To elucidate the role of FABP5 in lipid metabolism, the production of the FABP5 protein in a human RPE cell line was inhibited using RNA interference technology. As a result, the levels of cholesterol and cholesterol ester were decreased by about 40%, whereas FFAs and triglycerides were increased by 18 and 67% after siRNA treatment, respectively. Some species of phospholipids were decreased in siRNA-treated cells. Cellular lipid droplets were evident and apoB secretion was decreased by 76% in these cells. Additionally, we discovered that ARPE-19 cells could synthesize and secrete Apolipoprotein B100 (apoB100), which may serve as a backbone structure for the formation of lipoprotein particles in these cells. Our results indicate that FABP5 mRNA knockdown results in the accumulation of cellular triglycerides, decreased cholesterol levels, and reduced secretion of apoB100 protein and lipoprotein-like particles. These observations indicated that FABP5 plays a critical role in lipid metabolism in RPE cells, suggesting that FABP5 downregulation in the RPE/choroid complex in vivo might contribute to aging and early age-related macular degeneration.

Hepatitis C virus: viral proteins on the move

There is now increasing evidence that LDs (lipid droplets) play a central role in the production of infectious HCV (hepatitis C virus) and participate in virus assembly. Two viral proteins, namely core, which forms the capsid, and NS5A (non-structural 5A protein), a component of complexes engaged in viral RNA synthesis, are detected at LD surfaces in infected cells. Interactions between the two proteins may be critical for anchoring RNA replication sites to droplets for initiating virus assembly. The requirements for targeting of core in particular has received considerable attention since the nature of its interaction with LDs could play a key role in determining the efficiency of virion production. As well as attaching to droplets, core is able to alter their intracellular distribution and direct them towards the microtubule organizing centre. Inhibitors that disrupt microtubules block this redistribution by core and there is a concomitant decrease in virus production. Therefore altered dynamics of LDs may contribute to HCV assembly and release. The purpose of targeting LDs by HCV may be linked to their contribution to the formation of VLDLs (very-low-density lipoproteins) in hepatocytes since virus circulating in infected patients is associated with lipoprotein. Thus HCV may utilize the role played by LDs in the formation of lipoprotein particles as part of its life cycle and access this pathway by direct interaction of viral components with these intracellular storage organelles.

ATP-Binding Cassette Transporter A1 Expression and Apolipoprotein A-I Binding Are Impaired in Intima-Type Arterial Smooth Muscle Cells

Accumulation of excess cholesterol by intimal arterial smooth muscle cells (SMCs) contributes to the formation of foam cells in atherosclerotic lesions. The purpose of this study was to examine the expression and activity of ATP-binding cassette transporter A1 (ABCA1) in model intimal and medial arterial SMCs, in human atherosclerotic coronary artery intimal and medial layers, and in human intimal and medial SMCs. Model intimal arterial SMCs showed increased cholesteryl ester accumulation, absence of apolipoprotein A-I-mediated lipid efflux, markedly diminished ABCA1 expression, and poor apoA-I binding compared with medial-layer SMCs. Total ABCA1 mRNA and SMC-specific ABCA1 protein levels were diminished in the intimal layer compared with the medial layer of atherosclerotic human coronary arteries. Increased expression of ABCA1 by liver X receptor agonist treatment or gene transfection failed to correct apolipoprotein A-I binding, lipid efflux, or high-density lipoprotein particle formation by intima-type SMCs. In addition to impaired ABCA1 expression, intima-type SMCs appear to lack a critical binding factor or factors required for the apolipoprotein A-I-ABCA1 interaction, cholesterol efflux, and high-density lipoprotein particle formation. ABCA1 expression is reduced in cultured model intimal and human atherosclerotic lesion SMCs, suggesting that reduced ABCA1 activity contributes to smooth muscle foam cell formation in the intima.

Sialic acid moiety of apolipoprotein E and its impact on the formation of lipoprotein particles in human cerebrospinal fluid

Background Apolipoprotein (apo) E in the cerebrospinal fluid (CSF) is abundant with sialic acid (SA), and sialylation of certain proteins is known to modulate biological function. The aim of the present study was to quantify the SA content in CSF apoE and carry out the more detailed characterization of the CSF apoE-containing lipoproteins. Methods The method for the determination of the SA in CSF apoE was based on the conversion of SA into p-aminobenzoic acid ethyl ester-derivatized N-acetylmannosamine, followed by HPLC analysis. Results The levels of CSF SA and serum SA were 25.9 ± 1.5 and 2209 ± 196 μmol/l, respectively; however, when the SA values were corrected by the total protein concentrations, CSF SA values were approximately 3.5-fold of those in the serum. The SA levels in the CSF apoE-containing lipoprotein fractions were 5.3 ± 1.3% of total CSF SA, and were correlated with the CSF apoE concentrations. However, the ratios of SA to apoE were inversely proportional to the CSF lipid concentrations. The lipoprotein particle sizes were larger when the ratios of SA to CSF apoE were greater. Conclusion The SA moiety of the CSF apoE molecules may affect the formation of the apoE-containing lipoprotein particles and the regulation of lipid delivery in CNS.

Different Apolipoproteins Impact Nanolipoprotein Particle Formation

Spontaneous interaction of purified apolipoproteins and phospholipids results in formation of lipoprotein particles with nanometer-sized dimensions; we refer to these assemblies as nanolipoprotein particles or NLPs. These bilayer constructs can serve as suitable mimetics of biological membranes and are fully soluble in aqueous environments. We made NLPs from dimyristoylphospatidylcholine (DMPC) in combination with each of four different apolipoproteins: apoA-I, Delta-apoA-I fragment, apoE4 fragment, and apolipophorin III (apoLp-III) from the silk moth B. mori. Predominately discoidal in shape, these particles have diameters between 10 and 20 nm, share uniform heights between 4.5 and 5 nm, and can be produced in yields ranging between 40 and 60%. The particular lipoprotein, the lipid to lipoprotein ratio, and the assembly parameters determine the size and homogeneity of nanolipoprotein particles and indicate that apoA-I NLP preparations are smaller than the larger apoE422K and apoLp-III NLP preparations.

Correction of Apolipoprotein A-I-mediated Lipid Efflux and High Density Lipoprotein Particle Formation in Human Niemann-Pick Type C Disease Fibroblasts

Impaired cell cholesterol trafficking in Niemann-Pick type C (NPC) disease results in the first known instance of impaired regulation of the ATP-binding cassette transporter A1 (ABCA1), a lipid transporter mediating the rate-limiting step in high density lipoprotein (HDL) formation, as a cause of low plasma HDL-cholesterol in humans. We show here that treatment of human NPC1(-/-) fibroblasts with the liver X receptor (LXR) agonist TO-901317 increases ABCA1 expression and activity in human NPC1(-/-) fibroblasts, as indicated by near normalization of efflux of radiolabeled phosphatidylcholine and a marked increase in efflux of cholesterol mass to apoA-I. LXR agonist treatment prior to and during apoA-I incubation resulted in reduction in filipin staining of unesterified cholesterol in late endosomes/lysosomes, as well as cholesterol mass, in NPC1(-/-) cells. HDL species in human NPC disease plasma showed the same pattern of diminished large, cholesterol-rich alpha-1 HDL particles as seen in isolated heterozygous ABCA1 deficiency. Incubating NPC1(-/-) fibroblasts with the LXR agonist normalized the pattern of HDL particle formation by these cells. ABCG1, another LXR target gene involved in cholesterol efflux to HDL, also showed diminished expression in NPC1(-/-) fibroblasts and increased expression upon LXR agonist treatment. These results suggest that NPC1 mutations can be largely bypassed and that NPC1 protein function is non-essential for the trafficking and removal of cellular cholesterol if the down-stream defects in ABCA1 and ABCG1 regulation in NPC disease cells are corrected using an LXR agonist.

Dietary fatty acids differentially modulate messenger RNA abundance of low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and microsomal triglyceride transfer protein in Golden-Syrian hamsters

Dietary fatty acids modulate plasma and intracellular cholesterol concentrations. Circulating non–high-density lipoprotein cholesterol (nHDL-C) concentration is determined by rates of hepatic very low-density lipoprotein assembly and secretion, and clearance of subsequent metabolic products. The effect of dietary fat (butter, traditional margarine, soybean oil, and canola oil) was assessed with respect to plasma lipids, hepatic lipid composition, and messenger RNA (mRNA) abundance of low-density lipoprotein (LDL) receptor, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, sterol regulatory element-binding protein (SREBP) 2, and microsomal triglyceride transfer protein (MTP) in the Golden-Syrian hamster (Charles River Laboratories, Wilmington, MA). Hamsters were fed with a nonpurified diet (6.25 fat g/100 g) with 0.1 g cholesterol/100 g (control diet) or control diet with an additional 10 g experimental fat/100 g for 12 weeks. Hamsters fed with the control diet, unsaturated fats (canola and soybean oils), and margarine, relative to butter, had significantly lower total cholesterol and nHDL-C and triglyceride concentrations. Additional dietary fat, regardless of fatty acid profile, resulted in higher hepatic cholesterol concentrations. In contrast, relative to the control diet-, butter-, or margarine-fed hamsters, these changes were associated with a 4- and 8-fold higher LDL receptor and 5- and 9-fold higher SREBP mRNA abundance, in hamsters fed with canola and soybean oils, respectively. MTP mRNA, a marker of very low-density lipoprotein particle formation, was higher in canola- and soybean oil–fed hamsters relative to the control diet–fed hamsters, although differences were modest. These results suggest that the substitution of canola and soybean oils for butter results in lower nHDL-C concentrations that may be related to increased mRNA abundance of the LDL receptor, SREBP-2, and MTP genes.

The Role of Apolipoprotein A-I Helix 10 in Apolipoprotein-mediated Cholesterol Efflux via the ATP-binding Cassette Transporter ABCA1

Recent studies of Tangier disease have shown that the ATP-binding cassette transporter A1 (ABCA1)/apolipoprotein A-I (apoA-I) interaction is critical for high density lipoprotein particle formation, apoA-I integrity, and proper reverse cholesterol transport. However, the specifics of this interaction are unknown. It has been suggested that amphipathic helices of apoA-I bind to a lipid domain created by the ABCA1 transporter. Alternatively, apoA-I may bind directly to ABCA1 itself. To better understand this interaction, we created several truncation mutants of apoA-I and then followed up with more specific point mutants and helix translocation mutants to identify and characterize the locations of apoA-I required for ABCA1-mediated cholesterol efflux. We found that deletion of residues 221-243 (helix 10) abolished ABCA1-mediated cholesterol efflux from cultured RAW mouse macrophages treated with 8-bromo-cAMP. Point mutations in helix 10 that affected the helical charge distribution reduced ABCA1-mediated cholesterol efflux versus the wild type. We noted a strong positive correlation between cholesterol efflux and the lipid binding characteristics of apoA-I when mutations were made in helix 10. However, there was no such correlation for helix translocations in other areas of the protein as long as helix 10 remained intact at the C terminus. From these observations, we propose an alternative model for apolipoprotein-mediated efflux.

Apoprotein B100 has a prolonged interaction with the translocon during which its lipidation and translocation change from dependence on the microsomal triglyceride transfer protein to independence.

When lipid synthesis is limited in HepG2 cells, apoprotein B100 (apoB100) is not secreted but rapidly degraded by the ubiquitin-proteasome pathway. To investigate apoB100 biosynthesis and secretion further, the physical and functional states of apoB100 destined for either degradation or lipoprotein assembly were studied under conditions in which lipid synthesis, proteasomal activity, and microsomal triglyceride transfer protein (MTP) lipid-transfer activity were varied. Cells were pretreated with a proteasomal inhibitor (which remained with the cells throughout the experiment) and radiolabeled for 15 min. During the chase period, labeled apoB100 remained associated with the microsomes. Furthermore, by crosslinking sec61beta to apoB100, we showed that apoB100 remained close to the translocon at the same time apoB100-ubiquitin conjugates could be detected. When lipid synthesis and lipoprotein assembly/secretion were stimulated by adding oleic acid (OA) to the chase medium, apoB100 was deubiquitinated, and its interaction with sec61beta was disrupted, signifying completion of translocation concomitant with the formation of lipoprotein particles. MTP participates in apoB100 translocation and lipoprotein assembly. In the presence of OA, when MTP lipid-transfer activity was inhibited at the end of pulse labeling, apoB100 secretion was abolished. In contrast, when the labeled apoB100 was allowed to accumulate in the cell for 60 min before adding OA and the inhibitor, apoB100 lipidation and secretion were no longer impaired. Overall, the data imply that during most of its association with the endoplasmic reticulum, apoB100 is close to or within the translocon and is accessible to both the ubiquitin-proteasome and lipoprotein-assembly pathways. Furthermore, MTP lipid-transfer activity seems to be necessary only for early translocation and lipidation events.

Identification of Cysteine Pairs within the Amino-terminal 5% of Apolipoprotein B Essential for Hepatic Lipoprotein Assembly and Secretion

There is growing evidence that the amino-terminal globular domain of apolipoprotein B (apoB) is essential for lipoprotein particle formation in the hepatic endoplasmic reticulum. To identify the structural requirements for its function in lipoprotein assembly, cysteine (Cys) pairs required to form the seven disulfide bonds within the amino-terminal 21% of apoB were replaced in groups or individually by serine. Substitution of Cys pairs required for formation of disulfide bonds 1-3 or 4-7 (numbered from amino to carboxyl terminus) completely blocked the secretion of apoB28 in transfected HepG2 cells. To identify the specific disulfide bonds required for secretion, Cys pairs were mutated individually. Substitution of Cys pairs required for disulfide bonds 1, 3, 5, 6, or 7 had little or no impact on apoB28 secretion or buoyant density. In contrast, individual substitution of Cys pair 2 (amino acid residues 51 and 70) or 4 (218 and 234) severely inhibited apoB28 secretion and its capacity to undergo intracellular assembly with lipid. The same assembly and secretion defects were observed when these mutations were expressed as part of apoB50. These studies provide direct evidence that the ability of the internal lipophilic regions of apoB to engage in the recruitment and sequestration of lipid during translation is critically dependent upon a structural configuration contained within or affected by the amino-terminal 5% of the protein.

Dissociation of high density lipoprotein precursors from apolipoprotein B-containing lipoproteins in the presence of unesterified fatty acids and a source of apolipoprotein A-I.

Incubation of low (LDL), intermediate (IDL), or very low density lipoproteins (VLDL) with palmitic acid and either high density lipoproteins (HDL), delipidated HDL, or purified apolipoprotein (apo) A-I resulted in the formation of lipoprotein particles with discoidal structure and mean particle diameters ranging from 146 to 254 A by electron microscopy. Discs produced from IDL or LDL averaged 26% protein, 42% phospholipid, 5% cholesteryl esters, 24% free cholesterol, and 3% triglycerides; preparations derived from VLDL contained up to 21% triglycerides. ApoA-I was the predominant protein present, with smaller amounts of apoA-II. Crosslinking studies of discs derived from LDL or IDL indicated the presence of four apoA-I molecules per particle, while those derived from large VLDL varied more in size and contained as many as six apoA-I molecules per particle. Incubation of discs derived from IDL or LDL with purified lecithin:cholesterol acyltransferase (LCAT), albumin, and a source of free cholesterol produced core-containing particles with size and composition similar to HDL2b. VLDL-derived discs behaved similarly, although the HDL products were somewhat larger and more variable in size. When discs were incubated with plasma d greater than 1.21 g/ml fraction rather than LCAT, core-containing particles in the size range of normal HDL2a and HDL3a were also produced. A variety of other purified free fatty acids were shown to promote disc formation. In addition, some mono and polyunsaturated fatty acids facilitated the formation of smaller, spherical particles in the size range of HDL3c. Both discoidal and small spherical apoA-I-containing lipoproteins were generated when native VLDL was incubated with lipoprotein lipase in the presence of delipidated HDL. We conclude that lipolysis product-mediated dissociation of lipid-apoA-I complexes from VLDL, IDL, or LDL may be a mechanism for formation of HDL subclasses during lipolysis, and that the availability of different lipids may influence the type of HDL-precursors formed by this mechanism.

The mechanism of hyperlipidaemia in the nephrotic syndrome

The mechanism of hyperlipidaemia in the nephrotic syndrome has not been fully established. We propose that it results from hypoalbuminaemia due to inhibition of the reaction catalysed by lecithin cholesterol acyltransferase converting cholesterol of high density lipoproteins to cholesterol esters and to an inhibition of high density lipoprotein particle formation from very low density lipoproteins due to reduced activity of lipoprotein lipase.