Impact of Sepsis on High-Density Lipoprotein Metabolism

Background: High-density lipoproteins (HDL) are thought to play a protective role in sepsis through several mechanisms, such as promotion of steroid synthesis, clearing bacterial toxins, protection of the endothelial barrier, and antioxidant/inflammatory activities. However, HDL levels decline rapidly during sepsis, but the contributing mechanisms are poorly understood.Methods/Aim: In the present study, we investigated enzymes involved in lipoprotein metabolism in sepsis and non-sepsis patients admitted to the intensive care unit (ICU).Results: In 53 ICU sepsis and 25 ICU non-sepsis patients, we observed significant differences in several enzymes involved in lipoprotein metabolism. Lecithin-cholesterol acyl transferase (LCAT) activity, LCAT concentration, and cholesteryl transfer protein (CETP) activity were significantly lower, whereas phospholipid transfer activity protein (PLTP) and endothelial lipase (EL) were significantly higher in sepsis patients compared to non-sepsis patients. In addition, serum amyloid A (SAA) levels were increased 10-fold in sepsis patients compared with non-sepsis patients. Furthermore, we found that LCAT activity was significantly associated with ICU and 28-day mortality whereas SAA levels, representing a strong inflammatory marker, did not associate with mortality outcomes.Conclusion: We provide novel data on the rapid and robust changes in HDL metabolism during sepsis. Our results clearly highlight the critical role of specific metabolic pathways and enzymes in sepsis pathophysiology that may lead to novel therapeutics.

The extract of Ilex kudingcha inhibits atherosclerosis in apoE-deficient mice by suppressing cholesterol accumulation in macrophages

It was previously reported that oleanolic acid and ursolic acid, triterpenoid compounds occurring in Ilex kudingcha, ameliorate hyperlipidemia and atherosclerosis in apoE-deficient mice. In the present study, we investigated whether Ilex kudingcha extract exerts similar inhibitory effects on cholesterol accumulation in human monocyte-derived macrophages (HMDMs) and atherogenesis in apoE-deficient mice. Ilex kudingcha extract significantly inhibited cholesterol ester (CE) accumulation induced by acetyl-LDL (acetylated LDL) in HMDMs; however, it generated no effect on cell viability in HMDMs. Ilex kudingcha extract also suppressed CE accumulation in acyl-CoA: cholesterol acyl-transferase (ACAT)-overexpressing CHO (Chinese hamster ovary) cells, thereby indicating that it inhibits ACAT activity. Furthermore, the oral administration of Ilex kudingcha extract to apoE-deficient mice significantly decreased the levels of serum cholesterol, triglyceride, sLOX-1, as well as the regions of atherosclerotic lesions in the mice. Our study reveals crucial new-found evidence that Ilex kudingcha extract significantly inhibits ACAT activity and suppresses atherogenesis.

Gene Cascade Shift and Pathway Enrichment in Rat Kidney Induced by Acarbose Through Comparative Analysis

Acarbose is an effective anti-diabetic drug to treat type 2 diabetes mellitus (T2DM), a chronic degenerative metabolic disease caused by insulin resistance. The beneficial effects of acarbose on blood sugar control in T2DM patients have been confirmed by many studies. However, the effect of acarbose on patient kidney has yet to be fully elucidated. In this study, we report in detail the gene expression cascade shift, pathway and module enrichment, and interrelation network in acarbose-treated Rattus norvegicus kidneys based on the in-depth analysis of the GSE59913 microarray dataset. The significantly differentially expressed genes (DEGs) in the kidneys of acarbose-treated rats were initially screened out by comparative analysis. The enriched pathways for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were further identified. The protein-protein interaction (PPI) analysis for DEGs was achieved through the STRING database mining. Pathway interrelation and hub genes for enriched pathways were further examined to uncover key biological effects of acarbose. Results revealed 44 significantly up-regulated genes and 86 significantly down-regulated genes (130 significant differential genes in total) in acarbose-treated rat kidneys. Lipid metabolism pathways were considerably improved by acarbose, and the physical conditions in chronic kidney disease (CKD) patients were improved possibly through the increase of the level of high-density lipoprotein (HDL) by lecithin-cholesterol acyl-transferase (LCAT). These findings suggested that acarbose may serve as an ideal drug for CKD patients, since it not only protects the kidney, but also may relieve the complications caused by CKD.

Impaired cholesterol metabolism in the mouse model of cystic fibrosis. A preliminary study

This study aims to investigate cholesterol metabolism in a mouse model with cystic fibrosis (CF) by the comparison of affected homozygous versus wild type (WT) mice. In particular, we evaluated the effects of a diet enriched with cholesterol in both mice groups in comparison with the normal diet. To this purpose, beyond serum and liver cholesterol, we analyzed serum phytosterols as indirect markers of intestinal absorption of cholesterol, liver lathosterol as indirect marker of de novo cholesterol synthesis, liver cholestanol (a catabolite of bile salts synthesis) and the liver mRNA levels of LDL receptor (LDLR), 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR), acyl CoA:cholesterol acyl transferase 2 (ACAT2), cytochrome P450 7A1 (CYP7A1) and tumor necrosis factor alpha (TNFα). CF mice showed lower intestinal absorption and higher liver synthesis of cholesterol than WT mice. In WT mice, the cholesterol supplementation inhibits the synthesis of liver cholesterol and enhances its catabolism, while in CF mice we did not observe a reduction of LDLR and HMG-CoAR expression (probably due to an altered feed-back), causing an increase of intracellular cholesterol. In addition, we observed a further increase (5-fold) in TNFα mRNA levels. This preliminary study suggests that in CF mice there is a vicious circle in which the altered synthesis/secretion of bile salts may reduce the digestion/absorption of cholesterol. As a result, the liver increases the biosynthesis of cholesterol that accumulates in the cells, triggering inflammation and further compromising the metabolism of bile salts.

General perspectives for the treatment of atherosclerosis

: Atherosclerosis, a cardiovascular disease, is at the top of the list among the diseases leading to death. Although the biochemical and pathophysiological cascades involved within the development of atherosclerosis have been identified clearly, its nature is quite complex to be treated with a single agent targeting a pathway. Therefore, many natural and synthetic compounds have been suggested for the treatment of the disease. Majority of the drugs employed target one of the single components of the pathological outcomes, resulting in many times less effective and long-term treatments. In most cases, treatment options prevent further worsening of the symptoms rather than a radical treatment. Consequently, the current review has been prepared to focus on the validated and non-validated targets of atherosclerosis as well as the alternative treatment options such as hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, acyl-CoA cholesterol acyl transferase (ACAT) inhibitors, lipoprotein lipase stimulants, bile acid sequestrants, and some antioxidants. Related to the topic, both synthetic compounds designed employing medicinal chemistry skills and natural molecules becoming more popular in drug development are scrutinized in this mini review.

Glucocorticoids impair HDL-mediated cholesterol efflux besides increased HDL cholesterol concentration: a proof of concept

Objective: Glucocorticoids (GC) are associated with increased cardiovascular morbidity despite increased HDL-C concentration. HDL-mediated cholesterol efflux, a major anti-atherogenic property of HDL particles, is negatively associated with CVD risk. We aimed to determine whether HDL-mediated cholesterol efflux was influenced by GC. Design: Prospective, observational study. Methods: Lipid parameters, HDL composition, HDL-mediated cholesterol efflux, cholesteryl ester transfer protein, phospholipid transfer protein and lecithin cholesterol acyl-transferase (LCAT) activities were determined in ten patients with giant cell arteritis before and 3 months after GC introduction and in seven control subjects. HDL concentration and composition, HDL-mediated cholesterol efflux and LCAT activity were determined in GC-treated mice. Results: In patients, HDL-C concentration was higher after than before treatment GC-treatment (P = 0.002), while HDL-mediated cholesterol efflux was decreased (P = 0.008) and negatively associated with the proportion of cholesteryl ester in HDL (P = 0.04), independently of CRP. As well, in mice, HDL-C level was increased after GC exposure (P = 0.04) and HDL-mediated cholesterol efflux decreased (P = 0.04). GC-treated patients had higher cholesteryl ester content in HDL, higher HDL2-to-HDL3 ratio and higher LCAT activity than before treatment (P = 0.008, P = 0.02 and P = 0.004, respectively). Conclusions: We report, for the first time, that in patients with giant cell arteritis and mice treated with GC, HDL-mediated cholesterol efflux was impaired by GC besides an increased HDL-C level. This impaired HDL functionality, possibly related to HDL enrichment in cholesteryl ester, could contribute to the increased CVD risk observed in GC-treated patients. Further studies are needed in larger populations, to further decipher the effect of GC on HDL.

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