Thapsigargin and Tunicamycin Block SARS-CoV-2 Entry into Host Cells via Differential Modulation of Unfolded Protein Response (UPR), AKT Signaling, and Apoptosis.

BACKGROUND: SARS-Co-V2 infection can induce ER stress-associated activation of unfolded protein response (UPR) in host cells, which may contribute to the pathogenesis of COVID-19. To understand the complex interplay between SARS-Co-V2 infection and UPR signaling, we examined the effects of acute pre-existing ER stress on SARS-Co-V2 infectivity. METHODS: Huh-7 cells were treated with Tunicamycin (TUN) and Thapsigargin (THA) prior to SARS-CoV-2pp transduction (48 h p.i.) to induce ER stress. Pseudo-typed particles (SARS-CoV-2pp) entry into host cells was measured by Bright GloTM luciferase assay. Cell viability was assessed by cell titer Glo® luminescent assay. The mRNA and protein expression was evaluated by RT-qPCR and Western Blot. RESULTS: TUN (5 µg/mL) and THA (1 µM) efficiently inhibited the entry of SARS-CoV-2pp into host cells without any cytotoxic effect. TUN and THA's attenuation of virus entry was associated with differential modulation of ACE2 expression. Both TUN and THA significantly reduced the expression of stress-inducible ER chaperone GRP78/BiP in transduced cells. In contrast, the IRE1-XBP1s and PERK-eIF2α-ATF4-CHOP signaling pathways were downregulated with THA treatment, but not TUN in transduced cells. Insulin-mediated glucose uptake and phosphorylation of Ser307 IRS-1 and downstream p-AKT were enhanced with THA in transduced cells. Furthermore, TUN and THA differentially affected lipid metabolism and apoptotic signaling pathways. CONCLUSIONS: These findings suggest that short-term pre-existing ER stress prior to virus infection induces a specific UPR response in host cells capable of counteracting stress-inducible elements signaling, thereby depriving SARS-Co-V2 of essential components for entry and replication. Pharmacological manipulation of ER stress in host cells might provide new therapeutic strategies to alleviate SARS-CoV-2 infection.

Association of Advanced Lipoprotein Subpopulation Profiles with Insulin Resistance and Inflammation in Patients with Type 2 Diabetes Mellitus.

Plasma lipoproteins exist as several subpopulations with distinct particle number and size that are not fully reflected in the conventional lipid panel. In this study, we sought to quantify lipoprotein subpopulations in patients with type 2 diabetes mellitus (T2DM) to determine whether specific lipoprotein subpopulations are associated with insulin resistance and inflammation markers. The study included 57 patients with T2DM (age, 61.14 ± 9.99 years; HbA1c, 8.66 ± 1.60%; mean body mass index, 35.15 ± 6.65 kg/m2). Plasma lipoprotein particles number and size were determined by nuclear magnetic resonance spectroscopy. Associations of different lipoprotein subpopulations with lipoprotein insulin resistance (LPIR) score and glycoprotein acetylation (GlycA) were assessed using multi-regression analysis. In stepwise regression analysis, VLDL and HDL large particle number and size showed the strongest associations with LPIR (R2 = 0.960; p = 0.0001), whereas the concentrations of the small VLDL and HDL particles were associated with GlycA (R2 = 0.190; p = 0.008 and p = 0.049, respectively). In adjusted multi-regression analysis, small and large VLDL particles and all sizes of lipoproteins independently predicted LPIR, whereas only the number of small LDL particles predicted GlycA. Conventional markers HbA1c and Hs-CRP did not exhibit any significant association with lipoprotein subpopulations. Our data suggest that monitoring insulin resistance-induced changes in lipoprotein subpopulations in T2DM might help to identify novel biomarkers that can be useful for effective clinical intervention.

Differential Regulation of Glucosylceramide Synthesis and Efflux by Golgi and Plasma Membrane Bound ABCC10.

Glucosylceramide (GlcCer) synthesis by the enzyme glucosylceramide synthase (GCS) occurs on the cytosolic leaflet of the Golgi and is the first important step for the synthesis of complex glycosphingolipids (GSLs) that takes place inside the lumen. Apart from serving as a precursor for glycosylation, newly synthesized GlcCer is also transported to the plasma membrane and secreted onto HDL in the circulation. The mechanism by which GlcCer is transported to HDL remains unclear. Recently, we showed that ATP-binding cassette transporter protein C10 (ABCC10) plays an important role in the synthesis and efflux of GlcCer in Huh-7 cells. In this study, we found that treatment of Huh-7 cells with an ABCC10 inhibitor, sorafenib, decreased the synthesis and efflux of GlcCer. However, treatment of cells with cepharanthine reduced only the efflux, but not synthesis, of GlcCer. These results indicate that ABCC10 may regulate the synthesis and efflux of GlcCer differentially in liver cells.

ATP-Binding Cassette Protein ABCC10 Deficiency Prevents Diet-Induced Obesity but Not Atherosclerosis in Mice.

Excess plasma lipid levels are a risk factor for various cardiometabolic disorders. Studies have shown that improving dyslipidemia lowers the progression of these disorders. In this study, we investigated the role of ATP-binding cassette transporter C10 (ABCC10) in regulating lipid metabolism. Our data indicate that deletion of the Abcc10 gene in male mice results in lower plasma and intestinal triglycerides by around 38% and 36%, respectively. Furthermore, deletion of ABCC10 ameliorates diet-induced obesity in mice and leads to a better response during insulin and glucose tolerance tests. Unexpectedly, ABCC10 deficiency does not affect triglyceride levels or atherosclerosis in ApoE-deficient mice. In addition, our studies demonstrate low oleate uptake by enterocytes (~25-30%) and less absorption (~37%) of triglycerides in the small intestine of ABCC10 knockout mice. Deletion of the Abcc10 gene also alters several lipid metabolism genes in the intestine, suggesting that ABCC10 regulates dietary fat absorption, which may contribute to diet-induced obesity in mice.

Reduction in Insulin Mediated ERK Phosphorylation by Palmitate in Liver Cells Is Independent of Fatty Acid Induced ER Stress.

Saturated free fatty acids (FFAs) such as palmitate in the circulation are known to cause endoplasmic reticulum (ER) stress and insulin resistance in peripheral tissues. In addition to protein kinase B (AKT) signaling, extracellular signal-regulated kinase (ERK) has been implicated in the development of insulin resistance. However, there are conflicting data regarding role of ERK signaling in ER stress-induced insulin resistance. In this study, we investigated the effects of ER stress on insulin resistance and ERK phosphorylation in Huh-7 cells and evaluated how oleate prevents palmitate-mediated ER stress. Treatment with insulin resulted in an increase of 38-45% in the uptake of glucose in control cells compared to non-insulin-treated control cells, along with an increase in the phosphorylation of AKT and ERK. We found that treatment with palmitate increased the expression of ER stress genes, including the splicing of X box binding protein 1 (XBP1) mRNA. At the same time, we observed a decrease in insulin-mediated uptake of glucose and ERK phosphorylation in Huh-7 cells, without any change in AKT phosphorylation. Supplementation of oleate along with palmitate mitigated the palmitate-induced ER stress but did not affect insulin-mediated glucose uptake or ERK phosphorylation. The findings of this study suggest that palmitate reduces insulin-mediated ERK phosphorylation in liver cells and this effect is independent of fatty-acid-induced ER stress.

Relationship between the Soluble F11 Receptor and Annexin A5 in African Americans Patients with Type-2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is characterized by endothelial dysfunction, increased thrombogenicity, and inflammation. The soluble human F11 receptor (sF11R) and annexin A5 (ANXA5) play crucial roles in inflammatory thrombosis and atherosclerosis. We examined the relationship between circulating sF11R and ANXA5 and their impact on endothelial function. The study included 125 patients with T2DM. Plasma levels of sF11R and ANXA5 were quantified by ELISA. Microvascular function was assessed using the vascular reactivity index (VRI). Large artery stiffness was assessed by carotid-femoral pulse wave velocity (PWV). Carotid intima-media thickness (CIMT) was assessed by B-mode ultrasound imaging. The mean age of patients in the study was 59.7 ± 7.8 years, 78% had hypertension, 76% had dyslipidemia, and 12% had CKD. sF11R correlated positively with ANXA5 levels (ß = 0.250, p = 0.005), and correlated inversely with VRI and total nitic oxide (NO), (ß = −0.201, p = 0.024; ß = −0.357, p = 0.0001, respectively). Multivariate regression analysis revealed that sF11R was independently associated with ANXA5 in the total population and in patients with HbA1c > 6.5% (ß = 0.366, p = 0.007; ß = 0.425, p = 0.0001, respectively). sF11R and ANXA5 were not associated with vascular outcome, suggesting that they may not be reliable markers of vascular dysfunction in diabetes. The clinical significance of sF11R/ANXA5 association in diabetes warrants further investigation in a larger population.

Lipid Raft Integrity and Cellular Cholesterol Homeostasis Are Critical for SARS-CoV-2 Entry into Cells.

Lipid rafts in cell plasma membranes play a critical role in the life cycle of many viruses. However, the involvement of membrane cholesterol-rich lipid rafts in the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into target cells is not well known. In this study, we investigated whether the presence of cholesterol-rich microdomains is required for the entry of SARS-CoV-2 into host cells. Our results show that depletion of cholesterol in the rafts by methyl-beta-cyclodextrin (MßCD) treatment impaired the expression of the cell surface receptor angiotensin-converting enzyme 2 (ACE2), resulting in a significant increase in SARS-CoV-2 entry into cells. The effects exerted by MßCD could be substantially reversed by exogenous cholesterol replenishment. In contrast, disturbance of intracellular cholesterol homeostasis by statins or siRNA knockdown of key genes involved in the cholesterol biosynthesis and transport pathways reduced SARS-CoV-2 entry into cells. Our study also reveals that SREBP2-mediated cholesterol biosynthesis is involved in the process of SARS-CoV-2 entry in target cells. These results suggest that the host membrane cholesterol-enriched lipid rafts and cellular cholesterol homeostasis are essential for SARS-CoV-2 entry into cells. Pharmacological manipulation of intracellular cholesterol might provide new therapeutic strategies to alleviate SARS-CoV-2 entry into cells.

Molecular Mechanisms of Sphingolipid Transport on Plasma Lipoproteins.

Sphingolipids are biomolecules with diverse physiological functions in signaling as well as plasma membrane structure. They are associated with either cellular membranes or plasma lipoproteins and any changes in their levels may contribute to certain metabolic diseases. Sphingolipids are evenly distributed in lipoproteins and may be used as prognostic and diagnostic markers. Mechanisms involved in the transport of sphingolipids have been recently explored and here we discuss the most recent advances in the molecular mechanisms of sphingolipids transport by lipoproteins. It has been shown that microsomal triglyceride transfer protein (MTP) and ATP-binding cassette transporter family A protein 1 (ABCA1) play an important role in plasma sphingolipid homeostasis. However, the exact mechanisms are not well known. Though much research has already been done to emphasize the impact of sphingolipids changes in many pathological disorders, understanding mechanisms by which circulating lipoproteins assist in transporting sphingolipids may provide novel information that may help in devising strategies to therapeutically target these pathways to treat various metabolic disorders.

Diet-induced differential effects on plasma lipids secretion by the inositol-requiring transmembrane kinase/endoribonuclease 1α.

Intestinal and hepatic lipid metabolism plays an essential role in regulating plasma lipid levels. These lipids are mobilized on apolipoprotein B (apoB)-containing lipoproteins and their plasma homeostasis is maintained by balancing production and catabolism. Microsomal triglyceride transfer protein (MTP) which is expressed mainly in the intestine and liver plays an essential role in regulating the assembly and secretion of apoB-lipoproteins. Any imbalance in the production or clearance of lipoproteins leads to hyperlipidemia which is a major risk factor for atherosclerosis, obesity, diabetes, and metabolic syndrome. Here, we identify a new role of inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) in the regulation of plasma lipids. We generated intestine specific IRE1α knockout mice to study whether intestinal IRE1α regulates plasma lipids by modulating intestinal lipid absorption. Intestine specific deletion of Ire1a gene in mice fed chow diet, significantly reduced plasma cholesterol and triglycerides by 29% and 43% in Ire1a-⁣/- mice (P < 0.01 & P < 0.001, respectively). These changes were not associated with any alteration of MTP activity nor its mRNA expression. On the other hand, Western diet increased plasma triglyceride by 37% (P < 0.01) without affecting total plasma cholesterol in Ire1a-⁣/- mice. Interestingly, this effect was associated with a significant increase in the intestinal MTP activity and its mRNA expression (25%, P < 0.01 and 70%, P < 0.05, respectively). Collectively, our findings reveal key role of intestinal IRE1α in the regulation of plasma lipids that may provide a therapeutic target for disorders of lipid metabolism.

Association between nitrated lipoproteins and vascular function in type 2 diabetes.

Higher levels of nitrated lipoproteins (NT-HDL and NT-LDL) were found in blood and atherosclerotic plaques of patients with coronary artery disease. We aimed to examine the relationship between plasma NT-HDL and NT-LDL and diabetic vascular dysfunction. The study included 125 African-American patients with T2DM. NT-HDL and NT-LDL were quantified by ELISA. Microvascular function was assessed by vascular reactivity index (VRI). Large artery stiffness was assessed by carotid-femoral pulse wave velocity (PWV). Carotid intima-media thickness (CIMT) was assessed by B-mode ultrasound imaging. In univariate analysis, NT-HDL was associated with VRI in total population and in patients with HbA1c more than or equal to 7.0 percent (beta= -0.178, p= 0.034; beta = -0.265, p= 0.042; respectively). In contrast, NT-LDL was associated with CIMT in total population and in patients with HbA1c more than 7.0 percent (beta = -0.205, p= 0.022; beta = -0.244, p= 0.042; respectively). Multivariable-adjusted regression analysis demonstrated that NT-HDL independently predicted VRI outcome in total population and in well-controlled patients (beta = -0.282, p= 0.014; beta = -0.400, p= 0.035, respectively). These results suggest that NT-HDL could be used as marker to identify diabetic patients at risk of developing early microvascular complications.

Regulation of Sphingolipid Metabolism by MicroRNAs: A Potential Approach to Alleviate Atherosclerosis.

The rapidly expanding field of bioactive lipids is exemplified by the many sphingolipids, which are structurally and functionally diverse molecules with significant physiologic functions. These sphingolipids are main constituents of cellular membranes and have been found associated with plasma lipoproteins, and their concentrations are altered in several metabolic disorders such as atherosclerosis, obesity, and diabetes. Understanding the mechanisms that regulate their biosynthesis and secretion may provide novel information that might be amenable to therapeutic targeting in the treatment of these diseases. Several sphingolipid synthesis genes have been targeted as potential therapeutics for atherosclerosis. In recent years, significant progress has been made in studying the role of microRNAs (miRNAs) in lipid metabolism. However, little effort has been made to investigate their role in sphingolipid metabolism. Sphingolipid biosynthetic pathways involve various enzymes that lead to the formation of several key molecules implicated in atherosclerosis, and the identification of miRNAs that regulate these enzymes could help us to understand these complex pathways better and may prove beneficial in alleviating atherosclerosis.

Epigenetic Regulation of ATP-Binding Cassette Protein A1 (ABCA1) Gene Expression: A New Era to Alleviate Atherosclerotic Cardiovascular Disease.

The most important function of high density lipoprotein (HDL) is its ability to remove cholesterol from cells and tissues involved in the early stages of atherosclerosis back to the liver for excretion. The ATP-binding cassette transporters ABCA1 and ABCG1 are responsible for the major part of cholesterol efflux to HDL in macrophage foam cells. Thus, promoting the process of reverse cholesterol transport (RCT) by upregulating mainly ABCA1 remains one of the potential targets for the development of new therapeutic agents against atherosclerosis. Growing evidence suggests that posttranscriptional regulation of HDL biogenesis as well as modulation of ABCA1 expression are under the control of several genetic and epigenetic factors such as transcription factor (TFs), microRNAs (miRNAs) and RNA-binding proteins (RBPs).These factors may act either individually or in combination to orchestrate ABCA1 expression. Complementary to our recent work, we propose an exploratory model for the potential molecular mechanism(s) underlying epigenetic signature of ABCA1 gene regulation. Such a model may hopefully provide the basic framework for understanding the epigenetic regulation of RCT and contribute to the development of novel therapeutic strategies to alleviate the burden of cardiovascular diseases (CVD).

Epigenetic regulation of genes involved in the reverse cholesterol transport through interaction with miRNAs.

microRNAs (miRNAs) are a group of small non-coding RNA molecules known to regulate target genes at the post-transcriptional level. miRNAs are implicated in the regulation of multiple pathophysiological processes including dyslipidemia, a major risk factor for atherosclerosis. Emerging evidence suggests that miRNAs act as a novel class of epigenetic regulators of high-density lipoproteins cholesterol (HDL-C) from synthesis to clearance contributing remarkably to the pathogenesis of atherosclerosis. Accumulating studies have revealed that miRNAs such as miR-33, miR-27, miR-144, miR-758 and miR-20 are involved in the post-transcriptional control of ABCA1, ABCG1 and SCARB1 genes regulatory network of the reverse cholesterol transport (RCT). These miRNAs have been shown to be central players in the impairment of RCT pathway leading to the development of atherosclerosis. In this article, we present most recent understanding of involvement of relevant miRNAs in different steps of HDL metabolism and RCT pathway. We also discuss some of the actual limitations to the promise of these miRNAs and perspectives on their translation to clinical settings.

Correction to: Current therapies in alleviating liver disorders and cancers with a special focus on the potential of vitamin D.

[This corrects the article DOI: 10.1186/s12986-018-0251-5.].

Current therapies in alleviating liver disorders and cancers with a special focus on the potential of vitamin D.

Background: Liver dysfunction is a topic of global concern with many advancing therapies being researched. Though vitamin D takes a center place, other therapies especially nutritional are also gaining ground. Vitamin D has gone beyond its role in skeletal disorders by showcasing its associations in other metabolic dysfunctions too. Result: Epidemiological evidences show a correlation between the status of vitamin D and different forms of cancer. Vitamin D receptors and alterations in gene expression appear decisive in the development of chronic liver disorders. Nutritional status therefore plays a significant role in avoiding the complications related to liver dysfunctions, making it mandatory in maintaining vitamin D sufficiency in the body. Therapies with omega-3 fatty acids, antioxidants, amino acids, steroids also render benefits which could be further explored. Recent research on the progression of certain forms of liver cancer using vitamin D analogs like Seocalcitol EB 1089 has shown good promise. Conclusion: The anti-inflammatory and immuno- regulatory properties of vitamin D makes its analogs, suitable candidates of better choice for the prevention and treatment of liver disorders and cancer.

The "forgotten" modified lipoprotein subspecies.

Insights from preclinical and clinical studies have attempted to highlight the importance of modified lipoprotein particles in the pathogenesis of cardiovascular diseases (CVD). However, evidence is not conclusive. Since there is a relative dearth of clinical research in collecting useful information from traditional advanced lipoproteins testing, this present editorial introduces the aim of a special issue on modified lipoproteins as potential biomarkers for CVD. This issue aims at gathering a selection of insightful articles that address major challenges related to potential clinical use of modified lipoproteins as new CVD biomarkers. The editors seek to promote better mobilization of lipoproteins measurement for the pursuit of sustainable CVD clinical outcome and development of potential biomarkers. Knowledge and progress in this particular field will certainly help answering questions about clinical relevance of circulating modified lipoprotein subspecies and their potential use for better patient care and disease prevention. We hope that, when taken together, the focus on modified lipoproteins will stimulate new vision and reveal study key aspects for better clinical data outcome and more effective therapeutic strategies.

Precipitating factors and targeted therapies in combating the perils of sickle cell disease--- A special nutritional consideration.

Nutritional research in sickle cell disease has been the focus in recent times owing to not only specific nutritional deficiencies, but also the improvements associated with less painful episodes. Though hydroxyurea remains the drug of choice, certain adverse health effects on long term supplementation makes room for researches of different compounds. Macro and micro nutrient deficiencies, along with vitamins, play an important role in not only meeting the calorific needs, but also reducing clinical complications and growth abnormalities. Symptoms of hyper protein metabolism, increased cell turnover, increased cardiac output, and appetite suppression due to enhanced cytokine production, might give us leads for better understanding of the mechanisms involved. Different nutritional approaches comprising of traditional herbal therapies, antioxidants, flavonoids, vitamins, minerals etc., reducing oxidative stress and blood aggregation, have been tried out to increase the health potential. Nutritional therapies may also serve complementary to the newer therapies using ozone, hematopoietic stem cell transplantation, antifungal medications, erythropoietin etc. Herein we try to present a holistic picture of the different patho-physiological mechanisms, and nutritional strategies adopted.

Human serum preß1-high density lipoprotein levels are independently and negatively associated with coronary artery diseases.

BACKGROUND: Serum preß1-high density lipoprotein (preß1-HDL) was defined by two-dimensional non-denaturing linear gel electrophoresis and apolipoprotein A-I immuno-blotting. Serum preß1-HDL seems to play an important role in reverse cholesterol transport, a well-known anti-atherosclerosis process. However, there are still debatable questions for its quantification and coronary artery disease (CAD) relevance. METHODS: We isolated the preß1-HDL using a new native polyacrylamide gel electrophoresis (PAGE) system and lipid pre-staining serum. We established a two-demensional gel electrophoresis system. RESULTS: We measured the preß1-HDL in Tangier disease patients and subjects with cholesterol ester transfer protein (CETP) mutation. The preß1-HDL is clearly separated from lipid-free apoA-I monomer and cannot be converted into other HDL particles under lecithin-cholesterol acyltransferase (LCAT) inhibition. This preß1-HDL is a spheroidal particle with the highest apoA-1/cholesterol ratio and highest density (≥1.21 g/ml), as compared with all other HDLs. Importantly, we found that serum from subjects with Tangier disease or with cholesterol ester transfer protein (CETP) mutation have no detectible preß1-HDL particles. We recruited a total of 102 subjects underwent diagnostic coronary angiography and measured their preß1-HDL levels. Among them, 56 had no stenosis of coronary artery and 46 were diagnosed as CAD, which was predefined as the presence of a luminal diameter stenosis ≥50 % in at least 1 major coronary artery territory. We found that preß1-HDL is independently and negatively associated with the severity of the coronary artery stenosis (Gensini score). CONCLUSION: We established a novel and simple method for human serum preß1-HDL quantification. We found that human lower preß1-HDL is an independent predictor for severer coronary artery stenosis.

Mice subjected to aP2-Cre mediated ablation of microsomal triglyceride transfer protein are resistant to high fat diet induced obesity.

BACKGROUND: Microsomal triglyceride transfer protein (MTP) is essential for the assembly of lipoproteins. MTP has been shown on the surface of lipid droplets of adipocytes; however its function in adipose tissue is not well defined. We hypothesized that MTP may play critical role in adipose lipid droplet formation and expansion. METHODS: Plasmids mediated overexpression and siRNA mediated knockdown of Mttp gene were performed in 3T3-L1 pre-adipocytes to evaluate the effects of MTP on cell differentiation and triglyceride accumulation. Adipose-specific knockdown of MTP was achieved in mice bybreeding MTP floxed (Mttp (fl/fl) ) mice with aP2-Cre recombinase transgenic mice. Adipose-specific MTP deficient (A-Mttp (-/-) ) mice were fed 60 % high-fat diet (HFD), and the effects of MTP knockdown on body weight, body fat composition, plasma and tissues lipid composition, glucose metabolism, lipogenesis and intestinal absorption was studied. Lipids were measured in total fasting plasma and size fractionated plasma using colorimetric assays. Gene expression was investigated by Real-Time quantitative PCR. All data was assessed using t-test, ANOVA. RESULTS: MTP expression increased during early differentiation in 3T3-L1 cells, and declined later. The increases in MTP expression preceded PPARγ expression. MTP overexpression enhanced lipid droplets formation, and knockdown attenuated cellular lipid accumulation. These studies indicated that MTP positively affects adipogenesis. The ablation of the Mttp gene using aP2-Cre (A-Mttp (-/-) ) in mice resulted in a lean phenotype when fed a HFD. These mice had reduced white adipose tissue compared with wild-type Mttp (fl/fl) mice. The adipose tissue of A-Mttp (-/-) mice had increased number of smaller size adipocytes and less macrophage infiltration. Further, these mice were protected from HFD-induced fatty liver. The A-Mttp (-/-) mice had moderate increase in plasma triglyceride, but normal cholesterol, glucose and insulin levels. Gene expression analysis showed that the adipose tissue of the A-Mttp (-/-) mice had significantly lower mRNA levels of PPARγ and its downstream targets. CONCLUSION: These data suggest that MTP might modulate adipogenesis by influencing PPARγ expression, and play a role in the accretion of lipids to form larger lipid droplets. Thus, agents that inactivate adipose MTP may be useful anti-obesity drugs.

Nitrated apolipoprotein AI/apolipoprotein AI ratio is increased in diabetic patients with coronary artery disease.

AIMS/HYPOTHESIS: Recent studies have suggested that determination of HDL function may be more informative than its concentration in predicting its protective role in coronary artery disease (CAD). Apolipoprotein AI (apoAI), the major protein of HDL, is nitrosylated in vivo to nitrated apoAI (NT-apoAI) that might cause dysfunction. We hypothesized that NT-apoAI/apoAI ratio might be associated with diabetes mellitus (DM) in CAD patients. METHODS: We measured plasma NT-apoAI and apoAI levels in 777 patients with coronary artery disease (CAD) by ELISA. Further, we measured plasma cholesterol efflux potential in subjects with similar apoAI but different NT-apoAI levels. RESULTS: We found that median NT-apoAI/apoAI ratio was significantly higher in diabetes mellitus (DM) (n = 327) versus non-diabetic patients (n = 450). Further analysis indicated that DM, thiobarbituric acid-reactive substances and C-reactive protein levels were independent predictors of higher NT-apoAI/apoAI ratio. There was negative correlation between NT-apoAI/apoAI and use of anti-platelet and lipid lowering drugs. The cholesterol efflux capacity of plasma from 67 individuals with differing NT-apoAI but similar apoAI levels from macrophages in vitro was negatively correlated with NT-apoAI/apoAI ratio. CONCLUSIONS: Higher NT-apoAI/apoAI ratio is significantly associated with DM in this relatively large German cohort with CAD and may contribute to associated complications by reducing cholesterol efflux capacity.