ApoE and apoC-III-defined HDL subtypes: A descriptive study of their lecithin cholesterol acyl transferase and cholesteryl ester transfer protein content and activity

Background The functionality of high-density lipoproteins (HDL) is a better cardiovascular risk predictor than HDL concentrations. One of the key elements of HDL functionality is its apolipoprotein composition. Lecithin-cholesterol acyl transferase (LCAT) and cholesterol-ester transfer protein (CETP) are enzymes involved in HDL-mediated reverse cholesterol transport. This study assessed the concentration and activity of LCAT and CETP in HDL subspecies defined by their content of apolipoproteins E (apoE) and C-III (apoC-III) in humans. Methods Eighteen adults (ten women and eight men, mean age 55.6, BMI 26.9 Kg/m 2 , HbA1c 5.4%) were studied. HDL from each participant were isolated and divided into four subspecies containing respectively: No apoE and no apoC-III (E-C-), apoE but not apoC-III (E+C-), apoC-III but no apoE (E-C+) and both apoE and apoC-III (E+C+). The concentration and enzymatic activity of LCAT and CETP were measured within each HDL subspecies using immunoenzymatic and fluorometric methods. Additionally, the size distribution of HDL in each apolipoprotein-defined fraction was determined using non-denaturing electrophoresis and anti-apoA-I western blotting. Results HDL without apoE or apoC-III was the predominant HDL subtype. The size distribution of HDL was very similar in all the four apolipoprotein-defined subtypes. LCAT was most abundant in E-C- HDL (3.58 mg/mL, 59.6 % of plasma LCAT mass), while HDL with apoE or apoC-III had much less LCAT (19.8%, 12.2% and 8.37% of plasma LCAT respectively for E+C-, E-C+ and E+C+). LCAT mass was lower in E+C- HDL relative to E-C- HDL, but LCAT activity was similar in both fractions, signaling a greater activity-to-mass ratio associated with the presence of apoE. Both CETP mass and CETP activity showed only slight variations across HDL subspecies. There was an inverse correlation between plasma LCAT activity and concentrations of both E-C+ pre-beta HDL (r=-0.55, P =0.017) and E-C- alpha 1 HDL (r=-0.49, P =0.041). Conversely, there was a direct correlation between plasma CETP activity and concentrations of E-C+ alpha 1 HDL (r=0.52, P =0.025). Conclusions The presence of apoE in small HDL is correlated with increased LCAT activity and esterification of plasma cholesterol. These results favor an interpretation that LCAT and apoE interact to enhance anti-atherogenic pathways of HDL.

ApoE and apoC-III-defined HDL subtypes: A descriptive study of their LCAT and CETP content and activity

Background High-density lipoproteins (HDL) functionality predicts cardiovascular risk better than HDL concentrations. The apolipoprotein composition of HDL may be a determinant of their function. Lecithin-cholesterol acyl transferase (LCAT) and cholesterol-ester transfer protein (CETP) are key enzymes for HDL-mediated reverse cholesterol transport. We assessed the distribution and activity of LCAT and CETP in HDL subspecies defined by their content of apolipoproteins E (apoE) and C-III (apoC-III) in humans. Methods We isolated in 18 adult humans of both sexes (mean age 55.6, BMI 26.9 Kg/m2, HbA1c 5.4%), four subspecies of HDL containing respectively: No apoE and no apoC-III (E-C-), apoE but not apoC-III (E+C-), apoC-III but no apoE (E-C+) and both apoE and apoC-III (E+C+). In each HDL subspecies, we measured LCAT and CETP concentration and activity using immunoenzymatic and fluorometric methods. Additionally, we determined the size distribution of HDL in each apolipoprotein-defined fraction using non-denaturing electrophoresis and anti-ApoA-I western blot. Results Similar to previous studies, HDL in the E-C- fraction was the predominant subtype. The size distribution of HDL was very similar across all four apolipoprotein-defined fractions. LCAT was most abundant in E-C- HDL (3.58 mg/mL, 59.6 % of plasma LCAT mass), while HDL with apoE or apoC-III had much less LCAT (19.8%, 12.2% and 8.37% of plasma LCAT respectively for E+C-, E-C+ and E+C+). LCAT mass was lower in E+C- HDL relative to E-C- HDL, but LCAT activity was similar in both fractions, signaling a greater activity-to-mass ratio associated with the presence of apoE. Both CETP mass and CETP activity showed only slight variations across HDL subspecies. There was an inverse correlation between plasma LCAT activity and both E-C+ pre-beta HDL (r=-0.55, p=0.017) and E-C- alpha 1 HDL (r=-0.49, p=0.041). Conversely, there was a direct correlation between E-C+ alpha 1 HDL and CETP activity in plasma (r=0.52, p=0.025). Conclusions Our results suggest that LCAT activity in humans is influenced by the presence of small interchangeable apolipoproteins. The presence of apoE in small HDL is correlated with increased LCAT activity and esterification of plasma cholesterol.

Study of LCAT and some biochemical parameters in cardiovascular patient

The Clinical study included individuals (m23ales and females aged 25-75y) with cardiovascular disease. The activity of Lecithin: cholesterol acyl transferase (LCAT) and glutathione peroxidase(GPx) was estimated, in addition to the level of apolipoprotein AI (apo AI), apolipoprotein B100 (apoB100), total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-c), low density lipoprotein-cholesterol (LDL-c), glutathione (GSH), peroxy nitrate (PN), malondialdehyde (MDA), glucose and certain elements (Zn, Cu, Mg and Co) in blood serum. The results showed that there was a significant decrease in the activity of LCAT and GPx, and the level of apoAI, HDL-c, GSH, Zn and Mg. on the other hand, it was shown that there was a significant increase in the level of apoB100, TC, TG, LDL-c, PN, Glu, Cu and Co but on unsignificant change in the level of MDA for both male and females. http://dx.doi.org/10.25130/tjps.25.2020.026

ApoE and apoC-III-defined HDL subtypes: A descriptive study of their LCAT and CETP content and activity

Background High-density lipoproteins (HDL) in plasma are strongly and negatively associated with cardiovascular risk, yet interventions to raise HDL have not improved cardiovascular outcomes. HDL functionality and heterogeneity may hold the clue to this paradox. The apolipoprotein composition of HDL may be an important determinant of their functionality. Lecithin-cholesterol acyl transferase (LCAT) and cholesterol-ester transfer protein (CETP) are key enzymes for HDL-mediated reverse cholesterol transport. We assessed the distribution and activity of LCAT and CETP in HDL subspecies defined by their content of apolipoproteins E (apoE) and C-III (apoC-III) in humans. Methods We isolated in adult humans of both sexes (mean age 55.6, BMI 26.9 Kg/m2, HbA1c 5.4%), four subspecies of HDL containing respectively: No apoE and no apoC-III (E-C-), apoE but not apoC-III (E+C-), apoC-III but no apoE (E-C+) and both apoE and apoC-III (E+C+). In each HDL subspecies, we measured LCAT and CETP concentration and activity using immunoenzymatic and fluorometric methods. Additionally, we determined the size distribution of HDL in each apolipoprotein-defined fraction using non-denaturing electrophoresis and anti-ApoA-I western blot. Results Similar to previous studies, HDL in the E-C- fraction was the predominant subtype. The size distribution of HDL was very similar across all four apolipoprotein-defined fractions. LCAT was most abundant in E-C- HDL (3.58 mg/mL, 59.6 % of plasma LCAT mass), while HDL with apoE or apoC-III had much less LCAT (19.8%, 12.2% and 8.37% of plasma LCAT respectively for E+C-, E-C+ and E+C+). Despite a much lower LCAT mass, LCAT activity in E+C- HDL was comparable to that in E-C- HDL. Both CETP mass and CETP activity showed only slight variations across HDL subspecies. There was an inverse correlation between plasma LCAT activity and both E-C+ pre-beta HDL (r=-0.55, p=0.017) and E-C- alpha 1 HDL (r=-0.49, p=0.041). Conversely, there was a direct correlation between E-C+ alpha 1 HDL and CETP activity in plasma (r=0.52, p=0.025). Conclusions Our results suggest that LCAT activity in humans is influenced by the presence of small interchangeable apolipoproteins. The presence of apoE in small HDL is correlated with increased LCAT activity and esterification of plasma cholesterol.

Apolipoprotein C1: Its Pleiotropic Effects in Lipid Metabolism and Beyond

Apolipoprotein C1 (apoC1), the smallest of all apolipoproteins, participates in lipid transport and metabolism. In humans, APOC1 gene is in linkage disequilibrium with APOE gene on chromosome 19, a proximity that spurred its investigation. Apolipoprotein C1 associates with triglyceride-rich lipoproteins and HDL and exchanges between lipoprotein classes. These interactions occur via amphipathic helix motifs, as demonstrated by biophysical studies on the wild-type polypeptide and representative mutants. Apolipoprotein C1 acts on lipoprotein receptors by inhibiting binding mediated by apolipoprotein E, and modulating the activities of several enzymes. Thus, apoC1 downregulates lipoprotein lipase, hepatic lipase, phospholipase A2, cholesterylester transfer protein, and activates lecithin-cholesterol acyl transferase. By controlling the plasma levels of lipids, apoC1 relates directly to cardiovascular physiology, but its activity extends beyond, to inflammation and immunity, sepsis, diabetes, cancer, viral infectivity, and—not last—to cognition. Such correlations were established based on studies using transgenic mice, associated in the recent years with GWAS, transcriptomic and proteomic analyses. The presence of a duplicate gene, pseudogene APOC1P, stimulated evolutionary studies and more recently, the regulatory properties of the corresponding non-coding RNA are steadily emerging. Nonetheless, this prototypical apolipoprotein is still underexplored and deserves further research for understanding its physiology and exploiting its therapeutic potential.

Diabetes, Obesidad y Lípidos

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Abstract 588: Nuanced Antibody Responses to Apolipoprotein A-I in Patients With Cardiovascular Disease

Antibodies targeting apolipoprotein A-I (ApoA-I) have been identified in patients with cardiovascular disease (CVD). Anti-ApoA-I antibodies are thought to be markers of disease, but their exact role is unclear. We hypothesize that antibodies targeting ApoA-I are both protective and pathologic and unraveling the nuanced response to ApoA-I will provide insight into improved risk stratification of patients suffering from CVD. To test our hypothesis we screened serum samples by ELISA collected from patients with CVD to identify anti-ApoA-I antibody responses toward the full length protein along with immunogenic epitopes including the lecithin cholesterol acyl transferase (LCAT) domain and the C-terminal peptide of ApoA-I. These epitopes are of particular interest due to their propensity to undergo oxidative post-translational modification. Antibodies were affinity-purified toward ApoA-I, and their role in reverse cholesterol transport elucidated. Our data indicate that serum collected from patients with CVD enrolled in multiple clinical trials possess a highly nuanced immune response. We find that these antibody responses change over time in some patients who present with an AMI and antibodies correlate with outcomes. The mechanisms of these observed effects are currently under investigation. A full report on correlations between patient characteristic and antibody level will be presented. This work highlights the complexities of anti-ApoA-I antibodies in patients, which will guide development of a CVD risk stratification tool.