Triglyceride-rich Lipoprotein Remnants Research Articles

Low-Density Lipoprotein Receptor Signaling Mediates the Triglyceride-Lowering Action of Akkermansia muciniphila in Genetic-Induced Hyperlipidemia.

Akkermansia muciniphila (A muciniphila) is a mucin-degrading bacterium that resides in the mucus layer whose abundance inversely correlates with body weight and the development of diabetes mellitus in mice and humans. The objective of this study was to explore the regulatory effect of A muciniphila on host lipoprotein metabolism, insulin sensitivity, and hepatic metabolic inflammation. By establishing a novel mouse model that colonized the A muciniphila in the gastrointestinal tract of the cAMP-responsive binding protein H (CREBH)-deficient mouse and in vivo chylomicron assay, we found that increased colonization of A muciniphila in the gastrointestinal tract of wild-type mice protected mice from an acute fat load-induced hyperlipidemia compared with vehicle-treated mice. A muciniphila administration also significantly ameliorated chronic hypertriglyceridemia, improved insulin sensitivity, and prevented overproduction of postprandial chylomicrons in CREBH-null mice. Mechanistic studies revealed that increased A muciniphila colonization induced expression of low-density lipoprotein receptors and apolipoprotein E in the hepatocytes of CREBH-null mice, which facilitated the uptake of intermediate-density lipoprotein via the mediation of apolipoprotein B100 and apolipoprotein E, leading to the increased clearance of triglyceride-rich lipoprotein remnants, chylomicron remnants, and intermediate-density lipoproteins, from the circulation. Treatment with A muciniphila further improved hepatic endoplasmic reticulum stress and metabolic inflammation in CREBH-null mice. Increased colonization of the disease-protective gut bacteria A muciniphila protected the host from acute and chronic hyperlipidemia by enhancing the low-density lipoprotein receptor expression and alleviating hepatic endoplasmic reticulum stress and the inflammatory response in CREBH-null mice.

SLRP1ng Up Glucose: LRP1 Regulates Hepatic Insulin Responses

sLRP1ng Up Glucose: LRP1 Regulates Hepatic Insulin Responses

Abstract 18085: Heparan Sulfate Proteoglycans Only Modestly Affect Postprandial Hepatic Remnant Clearance in Humans

Introduction and Methods: Elevated circulating levels of Triglyceride-rich Remnant Lipoproteins (TLR) are strongly associated with increased risk for CVD. The hepatic clearance of TRL involves lipoprotein receptors i.e. the low-density lipoprotein receptor (LDLr) and heparin sulfate proteoglycans (HSPG). The relevance of each pathway in humans remains to be established. To further dissect the relative contribution of each of these receptors, we studied postprandial TRL metabolism with an oral fat tolerance test using cream supplemented with retinyl palmitate (RP) in 1) patients with a heterozygous loss-of-function (LOF) variant in LDLR stratified for a low (n=10) or high (n=10) HSPG gene score; 2) patients with heterozygous LOF variants in EXT1 or EXT2 (n=13), characterised by decreased HSPG chains length but normal sulfation pattern, and compared to matched healthy controls (n=13) and 3) diabetic patients (n=29) stratified for a functional SNP in SULF2, that predisposes to lower SULF2 expression and increased 6-O-sulfation of HSPG chains. Results: Postprandial TRL clearance was significantly delayed in patients with FH compared to controls (AUC-RP FH: 1971±190 vs Con: 646±110 nmol/l/h;P<0.0001 and iAUC-TG FH 6.9±1.0 vs Con 3.8±10 mmol/l/h, P<0.05) supporting the important role of LDLr in TRL clearance. No additional effect was observed if the FH group was stratified for HSPG gene score. Also, in patients with LOF variants in EXT, resulting in shorter HSPG chains, no difference in TRL clearance versus controls could be observed. In contrast, improved 6-O-sulfation due to lower hepatic protein expression of SULF2 resulted in improved fasting and postprandial TG levels and significantly lower iAUC-RP (iAUC-TG AA 6.9±1.1 vs GG 4.1±1.2 mmol/l/h P<0.05; AUC-RP AA 97±15 vs GG 15±2 mg/l/h; P<0.001) Conclusion: Our findings clearly indicate an important role for the LDLr in postprandial TRL clearance in humans. In contrast to murine studies, HSPGs do only modestly contribute to hepatic TRL clearance in humans, and implicate that sulfation of HSPG’s is of more relevance for TRL clearance than HSPG chain length.

Premature myocardial infarction is strongly associated with increased levels of remnant cholesterol

Remnant cholesterol has been defined as the cholesterol present in triglyceride-rich remnant lipoproteins. Elevated levels of remnant cholesterol have been associated with increased cardiovascular risk. Acute myocardial infarction (AMI) in very young individuals (≤40 years) represents a rare disease with a typical risk factor profile and a lipid phenotype that is characterized by a predominance of elevated triglyceride-rich lipoproteins. The aim of this study was to investigate the role of remnant cholesterol in premature AMI. We prospectively enrolled 302 patients into our multicenter case-control study comprising 102 consecutive myocardial infarction survivors (≤40 years) and 200 hospital controls. Myocardial infarction patients were frequency matched for age, gender, and center. Remnant cholesterol was calculated from standard lipid parameters. Remnant cholesterol was 1.7-fold higher in premature AMI patients compared with controls (61.1 ± 36.8 vs 35.8 ± 16.8 mg/dL; P < .001). Remnant cholesterol was the lipid fraction most strongly associated with premature myocardial infarction (odds ratio 3.87; 95% confidence interval 2.26-6.64; P < .001) for an increase of 1-standard deviation. This observation was independent from clinical risk factors and plasma lipid levels. Remnant cholesterol is strongly associated with premature myocardial infarction, can be easily calculated, and might serve as a new potent risk marker in this young patient population.

Dysbetalipoproteinemia: an extreme disorder of remnant metabolism.

Lipoprotein metabolism and the role of apolipoprotein E in the pathogenesis of dysbetalipoproteinemia. Remnant lipoproteins, modulated by lifestyle and genetic factors, are atherogenic. Dysbetalipoproteinemia could be viewed as a monogenic disorder of remnant metabolism. Elevated plasma triglyceride and cholesterol concentrations (mixed hyperlipidemias) are commonly encountered and dysbetaliproteinemia should be considered in this setting. Dysbetalipoproteinemia (remnant clearance disease, Fredrickson type III hyperlipidemia) is an uncommon dyslipoproteinemia related to mutations in apolipoprotein E that disrupt the clearance of remnants of triglyceride-rich lipoproteins; it may be overlooked because xanthomata of the skin and/or tendons occur in a minority of patients. The diagnosis ideally requires the demonstration of remnant lipoprotein accumulation and a genetic cause. Genotyping for apolipoprotein E2 may not prove the diagnosis as it may be associated with low plasma lipid values. The recent association of remnant lipoproteins with atherosclerosis along with many factors that modulate remnant lipoprotein metabolism underscores the importance of recognising dysbetalipoproteinemia as an extreme state of remnant lipoprotein accumulation. Although there may be some differences between remnants in the general population and dysbetalipoproteinemia, it is clear that remnants promote atherosclerosis. Current treatment strategies are adequate but new strategies could also be of benefit in dysbetalipoproteinemia.

Patients with type 1 diabetes show signs of vascular dysfunction in response to multiple high-fat meals.

BackgroundA high-fat diet promotes postprandial systemic inflammation and metabolic endotoxemia. We investigated the effects of three consecutive high-fat meals on endotoxemia, inflammation, vascular function, and postprandial lipid metabolism in patients with type 1 diabetes.MethodsNon-diabetic controls (n = 34) and patients with type 1 diabetes (n = 37) were given three high-caloric, fat-containing meals during one day. Blood samples were drawn at fasting (8:00) and every two hours thereafter until 18:00. Applanation tonometry was used to assess changes in the augmentation index during the investigation day.ResultsThree consecutive high-fat meals had only a modest effect on serum LPS-activity levels and inflammatory markers throughout the day in both groups. Of note, patients with type 1 diabetes were unable to decrease the augmentation index in response to the high-fat meals. The most profound effects of the consecutive fat loads were seen in chylomicron and HDL-metabolism. The triglyceride-rich lipoprotein remnant marker, apoB-48, was elevated in patients compared to controls both at fasting (p = 0.014) and postprandially (p = 0.035). The activities of the HDL-associated enzymes PLTP (p < 0.001), and CETP (p = 0.007) were higher and paraoxonase (PON-1) activity, an anti-oxidative enzyme bound to HDL, decreased in patients with type 1 diabetes (p = 0.027).ConclusionsIn response to high-fat meals, early signs of vascular dysfunction alongside accumulation of chylomicron remnants, higher augmentation index, and decreased PON-1 activity were observed in patients with type 1 diabetes. The high-fat meals had no significant impact on postprandial LPS-activity in non-diabetic subjects or patients with type 1 diabetes suggesting that metabolic endotoxemia may be more central in patients with chronic metabolic disturbances such as obesity, type 2 diabetes, or diabetic kidney disease.

PITAVASTATIN REDUCES REMNANT LIPOPROTEIN CHOLESTEROL SIGNIFICANTLY MORE THAN DOES PRAVASTATIN IN HIV-INFECTED SUBJECTS: THE INTREPID TRIAL

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in those with chronic HIV infection, due in part to HIV associated dyslipidemia. An emerging CVD risk factor is triglyceride-rich remnant lipoprotein cholesterol (RLP-C: the sum of IDL and VLDL3 cholesterol). The effects of

Abstract 18557: Lipid Phenotypes at the Extremes of HDL Cholesterol: Very Large Database of Lipids Study 9

Background: Patients with extreme levels of HDL-C may inform contemporary controversies in HDL metabolism and therapies. Aim: To characterize lipid phenotypes at extremes of HDL-C. Methods: We examined 136,746 U.S. adults and children from the Very Large Database of Lipids (Baltimore, MD; NCT01698489 ) who were clinically referred for a Vertical Auto Profile test (Birmingham, AL) of cholesterol subfractions from 2009 to 2011. We categorized patients at extreme levels of HDL-C into percentile categories (&lt;0.1 th , 0.1 th to &lt;1 st , 1 st to 5 th , 95 th to 99 th , &gt;99 th to 99.9 th , and &gt;99.9 th ). Within these groups, we examined HDL-C subclasses 2 and 3, LDL-C, LDL density, non-HDL-C, triglycerides, VLDL-C, and remnant lipoprotein cholesterol. Results: Patients had a mean age of 59±15 years and 52% were women. With increasing HDL-C percentile, there was monotonically rising HDL 2 -C/HDL 3 -C ratio, consistent with more cholesterol loaded HDL particles (Table, P&lt;0.0001). Triglycerides, VLDL-C, and remnant lipoprotein cholesterol levels decreased monotonically with rising HDL-C levels (P&lt;0.0001). LDL-C increased proportionally with VLDL-C decrease resulting in constant median non-HDL-C levels. There is a progressive increase in LDL density with decreasing HDL-C. In addition to these broad trends, there was within-group heterogeneity. Conclusion: Across a broad range of HDL-C, these findings illustrate the extensive interaction between HDL and triglyceride rich remnant lipoproteins, and LDL density, possibly mediating residual cardiovascular risk. Careful phenotyping will be crucial in selecting clinical trial populations for novel HDL-targeted therapies as patients with low and high HDL-C are not all one in the same.

Abstract 18730: Correlates and Cut-points of the Triglyceride/HDL Cholesterol Ratio: The Very Large Database of Lipids 4 (VLDL-4)

Background: An elevated TG/HDL-C is predictive of atherosclerotic cardiovascular disease; however, advanced lipoprotein correlates of the TG/HDL-C ratio and discrimination by standard cut-points are incompletely characterized. Hypothesis: Elevated TG/HDL-C correlates most strongly with triglyceride-rich remnant lipoprotein cholesterol (RLP-C) and also with LDL density, Lp(a)-C, and male gender. Methods: We examined 1,350,908 individuals from the Very Large Database of Lipids (Baltimore, MD; NCT01698489 ) who were clinically referred for lipoprotein cholesterol ultracentrifugation (Atherotech, Birmingham, AL). LDL density was assessed as a continuous LDL density parameter (LLDR) calculated as the natural log of the ratio of dense to buoyant LDL-C subfractions. RLP-C was defined as VLDL 3 -C plus IDL-C. Results: The strongest univariate correlates of the TG/HDL-C ratio were VLDL 3 -C (spearman rho= 0.824, p&lt;0.0001) and IDL-C (spearman rho=0.537, p&lt;0.0001). In a multivariable linear regression model including age, gender, LLDR, Lp(a)-C, VLDL 3 -C, and IDL-C, the overall adjusted R 2 was 0.764 (p&lt;0.0001). In this model, IDL-C was inversely correlated (partial R=-0.140, p&lt;0.0001) while VLDL 3 -C (partial R=0.697, p&lt;0.001) was more strongly and positively associated with TG/HDL-C. We compared demographic and lipid parameters across standard cut-points of TG/HDL-C (&lt;3, 3-5, &gt;5) ( Table ). Compared with the TG/HDL-C &lt;3 group, there was a 36% higher VLDL 3 -C level in those with a TG/HDL-C of 3-5, and 73% higher level in those with a TG/HDL-C &gt;5. There was a progressively higher LLDR across these groups characteristic of increasing LDL density. Conclusions: A higher TG/HDL ratio is correlated with an increasingly atherogenic lipid phenotype. Across increasing TG/HDL-C groups, VLDL 3 -C, IDL-C, and RLP-C increase. Non-HDL-C rises across these groups along with LDL density, despite similar LDL-C.

Demystifying the management of hypertriglyceridaemia

Hypertriglyceridaemia (typical triglyceride level 1.7-5.0 mmol/l) is caused by interactions between many genetic and nongenetic factors, and is a common risk factor for atherosclerotic cardiovascular disease (CVD). Patients with hypertriglyceridaemia usually present with obesity, insulin resistance, hepatic steatosis, ectopic fat deposition, and diabetes mellitus. Hypertriglyceridaemia reflects the accumulation in plasma of proatherogenic lipoproteins, triglyceride-rich lipoprotein (TRL) remnants, and small, dense LDL particles. Mendelian randomization studies and research on inherited dyslipidaemias, such as type III dysbetalipoproteinaemia, testify that TRLs are causally related to atherosclerotic CVD. Extreme hypertriglyceridaemia (a triglyceride level >20 mmol/l) is rare, often monogenic in aetiology, and frequently causes pancreatitis. Treatment of hypertriglyceridaemia relies on correcting secondary factors and unhealthy lifestyle habits, particularly poor diet and lack of exercise. Pharmacotherapy is indicated for patients with established CVD or individuals at moderate-to-high risk of CVD, primarily those with metabolic syndrome or diabetes. Statins are the cornerstone of treatment, followed by fibrates and n-3 fatty acids, to achieve recommended therapeutic levels of plasma LDL cholesterol, non-HDL cholesterol, and apolipoprotein (apo) B-100. The case for using niacin has been weakened by the results of clinical trials, but needs further investigation. Extreme hypertriglyceridaemia requires strict dietary measures, and patients with a diagnosis of genetic lipoprotein lipase deficiency might benefit from LPL gene replacement therapy. Several therapies for regulating TRL metabolism, including inhibitors of diacylglycerol O-acyltransferase and microsomal triglyceride transfer protein, and apoC-III antisense oligonucleotides, merit further investigation in patients with hypertriglyceridaemia.

Lipoprotein remnants and dense LDL are associated with features of unstable carotid plaque: A flag for non-HDL-C

ObjectiveWe investigated the association between cholesterol across the LDL density range and in the VLDL and IDL particles with the prevalence of inflammatory cells in plaques of patients with severe carotid artery stenosis. MethodsForty-five patients undergoing carotid endarterectomy were studied. Plaque specimens were analyzed for cellular composition by immunocytochemistry using monoclonal antibodies. Lipoprotein subclasses were separated by gradient ultracentrifugation. ResultsWe found no correlations between LDL-C, HDL-C and plasma triglyceride levels with plaque cellular composition. On the other hand, macrophage content was significantly related to cholesterol in the dense LDL subclasses (r = 0.30, p < 0.01) and in the triglyceride-rich lipoprotein remnants, namely dense VLDL and IDL particles (r = 0.46, p < 0.01). HDL subclasses were not correlated with plaque cellular composition. In a mirror manner, smooth muscle cells were inversely associated with cholesterol levels of the dense LDL subclasses (r = −0.32, p < 0.01 fraction 10; r = −0.26, p < 0.05 fraction 11) while only a non-significant trend was observed with the cholesterol in the VLDL-IDL fractions. These results provide the pathophysiological background to account for the relevance of non-HDL-C as the only lipid parameter, aside LDL density, significantly associated (β = 0.351, p = 0.021) with carotid plaque macrophage content. ConclusionsWe provide evidence that lipoprotein subclasses, specifically cholesterol in the dense LDL fractions and in the triglyceride-rich lipoprotein remnants, significantly affect carotid plaque cellular composition, in particular macrophages content.

805 Knockout of SULF2 Significantly Ameliorates Hypercholesterolemia, Steatohepatitis and Liver Fibrosis in Obese Mice Fed a Fast Food Diet

Background: Nonalcoholic fatty liver disease (NAFLD), an important consequence of metabolic disorders such as obesity and type 2 diabetes (T2DM), has become highly prevalent in the US, and is now an important public health concern. Recent reports have identified the heparan sulfate degrading endosulfatase sulfatase 2 (Sulf2) as a suppressor of triglyceriderich lipoprotein (TRL) remnant clearance by hepatocytes in T2DM mice, thus enhancing postprandial hypertriglyceridemia. Further, inhibition of Sulf2 normalized the VLDL-binding capacity of hepatocytes from T2DM mice and abolished postprandial hypertriglyceridemia. We hypothesized that an increase in hepatic Sulf2 occurring during insulin resistance states such as obesity and T2DM decreases hepatic clearance of TRL remnants and contributes to the development of NAFLD, which can be characterized by non-alcoholic steatohepatitis (NASH) and liver fibrosis. Aims: To investigate (1) whether a fast food diet high in saturated fats, cholesterol, and fructose can produce insulin resistance and overexpression of Sulf2; and (2) whether depletion of Sulf2 can protect against NASH and liver fibrosis in obese mice on a fast food diet. Methods: Sulf2 knockout and wild-type mice (n=12 each) were fed a fast food diet rich in saturated fats and cholesterol along with fructose in their drinking water or normal rodent chow with tap water, beginning at 6-8 weeks of age. At 9 months, mice were sacrificed, blood was obtained for assessment of insulin resistance, alanine transaminase (ALT) and serum lipids, and the livers were harvested and examined for steatosis, steatohepatitis, and fibrosis. Results: The fast food diet produced obesity and insulin resistance. Sulf2 knockout mice fed the fast food diet had significantly less weight gain and lower serum ALT, total cholesterol and LDL-cholesterol than wild-type mice (p,0.05). The fast food diet also induced histopathological features of NASH, including hepatic microvesicular steatosis, inflammation and fibrosis. Hepatic fibrosis was significantly decreased in Sulf2 knockout mice compared to controls (p,0.05). Conclusions: Depletion of Sulf2 improves hypercholesterolemia, steatohepatitis and hepatic fibrosis in a mouse model of NASH induced by a fast food diet. Inhibition of SULF2 may be a potential preventive and therapeutic strategy for NASH with progressive fibrosis.

Lipids and HCV

Chronic hepatitis C virus (HCV) infection is associated with an increase in hepatic steatosis and a decrease in serum levels of total cholesterol, low-density lipoprotein cholesterol (LDL) and apolipoprotein B (apoB), the main protein constituent of LDL and very low-density lipoprotein (VLDL). These changes are more marked in HCV genotype 3 infection, and effective treatment results in their reversal. Low lipid levels in HCV infection correlate not only with steatosis and more advanced liver fibrosis but also with non-response to interferon-based therapy. The clinical relevance of disrupted lipid metabolism reflects the fact that lipids play a crucial role in the life cycle of hepatitis C virus. HCV assembly and maturation in hepatocytes depend on microsomal triglyceride transfer protein and apoB in a manner that parallels the formation of VLDL. VLDL production from the liver occurs throughout the day with an estimated 10(18) particles produced every 24 h whilst the estimated hepatitis C virion production rate is 10(12) virions per day. HCV particles in the serum exist as a mixture of complete low-density infectious lipo-viral particles (LVP) and a vast excess of apoB-associated empty nucleocapsid-free sub-viral particles that are complexed with anti-HCV envelope antibodies. Apolipoprotein E (apoE) is also involved in HCV particle morphogenesis and is an essential apolipoprotein for HCV infectivity. ApoE is a critical ligand for the receptor-mediated removal of triglyceride rich lipoprotein (TRL) remnants by the liver. The dynamics of apoB-associated lipoproteins, including HCV-LVP, change post-prandially with an increase in large TRL remnants and very low density HCV-LVP which are rapidly cleared by the liver (at least three HCV receptors are cellular receptors for uptake of TRL remnants). In summary, HCV utilises triglyceride-rich lipoprotein pathways within the liver and the circulation to its advantage.

Impaired LDL Receptor-Related Protein 1 Translocation Correlates with Improved Dyslipidemia and Atherosclerosis in apoE-Deficient Mice

ObjectiveDetermination of the in vivo significance of LDL receptor-related protein 1 (LRP1) dysfunction on lipid metabolism and atherosclerosis development in absence of its main ligand apoE.Methods and ResultsLRP1 knock-in mice carrying an inactivating mutation in the NPxYxxL motif were crossed with apoE-deficient mice. In the absence of apoE, relative to LRP1 wild-type animals, LRP1 mutated mice showed an increased clearance of postprandial lipids despite a compromised LRP1 endocytosis rate and inefficient insulin-mediated translocation of the receptor to the plasma membrane, likely due to inefficient slow recycling of the mutated receptor. Postprandial lipoprotein improvement was explained by increased hepatic clearance of triglyceride-rich remnant lipoproteins and accompanied by a compensatory 1.6-fold upregulation of LDLR expression in hepatocytes. One year-old apoE-deficient mice having the dysfunctional LRP1 revealed a 3-fold decrease in spontaneous atherosclerosis development and a 2-fold reduction in LDL-cholesterol levels.ConclusionThese findings demonstrate that the NPxYxxL motif in LRP1 is important for insulin-mediated translocation and slow perinuclear endosomal recycling. These LRP1 impairments correlated with reduced atherogenesis and cholesterol levels in apoE-deficient mice, likely via compensatory LDLR upregulation.

Decrease in circulating fibroblast growth factor 21 after an oral fat load is related to postprandial triglyceride-rich lipoproteins and liver fat

Elevated levels of circulating fibroblast growth factor 21 (FGF21) are commonly encountered in type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease, all of which share exaggerated postprandial lipemia as a common proatherogenic feature. How FGF21 responds to an oral fat load in man is unknown. We measured liver fat contents and subcutaneous and visceral fat volumes in 47 healthy subjects, who also underwent an oral fat load with measurements of plasma FGF21 and free fatty acid (FFA). Triglyceride (TG), apolipoprotein B-48 (apoB-48), and apoB-100 concentrations were measured in triglyceride-rich lipoprotein (TRL) fractions. When compared with fasting levels, the concentration of FGF21 decreased significantly at 4 h (P < 0.05) and tended to return to fasting levels at 8 h after an oral fat load. Fasting and postprandial FGF21 correlated significantly with liver fat as well as with TRLs in the chylomicron and especially in very low-density lipoprotein 1 (VLDL1) and VLDL2 fractions representing remnant particles, but not with FFA. Subjects with increased liver fat (>5%, n = 12) showed impaired suppression of FGF21 at 4 h (P < 0.05) and at 8 h (P=0.01) and demonstrated higher postprandial TG area under the curve in plasma and TRL fractions (P ≤ 0.032) compared with those with normal liver fat (≤ 5%, n = 35). We observed a significant decrease of FGF21 concentration after an oral fat load. Fasting and postprandial FGF21 levels were closely related to large VLDL and remnants, but not to plasma FFA. Our pilot findings suggest that the postprandial accumulation of TRL remnants and liver fat may modulate postprandial FGF21 levels.

Why, when and how should hypertriglyceridemia be treated in the high-risk cardiovascular patient?

Recent epidemiology attests that hypertriglyceridemia may be a causal risk factor for cardiovascular disease (CVD). The specific atherogenicity of hypertriglyceridemia relates to the accumulation in plasma of triglyceride-rich lipoprotein remnants. Hypertriglyceridemia also drives a ‘global’ atherogenic dyslipidemic profile, which is frequent in high-risk cardiovascular patients, such as Type 2 diabetics. Elevated triglyceride in fasting or nonfasting blood samples should be a trigger for assessing atherogenic components of the lipid profile, particularly HDL-cholesterol, non-HDL-cholesterol and apoB. Residual risk of CVD remains high in statin-treated diabetic patients owing to persistent atherogenic dyslipidemia, which is not fully corrected by these agents nor by the addition of ezetimibe. Hypertriglyceridemia may then be targeted with niacin, fibrates or n-3 fatty acids, after correcting aggravating factors, especially obesity and hyperglycemia. Fibrates consistently decrease coronary events in dyslipidemic patients in outcome studies. New evidence supports adding fenofibrate to a statin in Type 2 diabetics with residual hypertriglyceridemia and low HDL-cholesterol; extrapolating from a recent meta-analysis, a 15% reduction in triglycerides could translate into a further 15% reduction in coronary events. Ongoing clinical trials may provide new evidence for adding niacin to a statin. The value of higher doses of n-3 fatty acids in reducing CVD risk remains to be demonstrated. The high triglyceride/low HDL nexus is an under-recognized risk factor for CVD that merits more detailed clinical assessment and treatment, particularly in patients with Type 2 diabetes already receiving a statin.

The 'interferon paradox' as a predictor of non-response to anti-viral therapy: novel association with apolipoprotein E and hepatitis C virus (HCV) lipoviralparticles (LVP).

Introduction Identification of factors that influence response to treatment are important for individualised care in the era of direct acting antivirals. Interferon-γ inducible protein-10 (IP10) is one of hundreds of interferon stimulated genes (ISGs). Paradoxically, high ISGs, notably IP10 are associated with poor treatment response. Although HCV hijacks the VLDL pathway in its life cycle, another paradox is that high LDL cholesterol is a marker of favourable outcome. We have shown that infectious HCV LVP correlate with insulin resistance and that high LVP ratio (LVP ratio = LVP/LVP + non LVP) is associated with lower EVR.1 Aim To evaluate the interactions between LVP, IP10 and lipid profiles. Methods Fasting samples were collected from 71 consecutive HCV G1 patients. LVP and LVP ratio were determined as previously described.1 Fasting lipids, apoB and apoE were measured using automated enzymatic methods. IP10 was measured using a commercially available ELISA (R&D Systems, Abingdon, UK). Results Univariate analysis demonstrated a relationship between IP10 and LVP ratio (r=0.31, p=0.028) but not between total viral load and IP10 (r=0.005, p=0.973). IP10 levels inversely correlated with LDL cholesterol (r=-0.302, p=0.017) and apoB (r=-0.295, p=0.015). IP10 levels also strongly positively correlated with apoE (r=0.444 p Conclusion This data indicates there is a close link between ISGs and lipoprotein metabolism. High IP10 correlates with apoE which is an exchangeable lipoprotein that transfers from HDL to triglyceride-rich lipoprotein remnants where it mediates clearance via LDLR, a candidate HCV receptor. ApoE is important in HCV replication/assembly and is a constituent of infectious LVP. Hence the effect of the endogenous interferon response on lipids is favourable to the virus by promoting LVP. This provides a possible explanation for the interferon paradox.

Abstract: 550 PLASMA TRIGLYCERIDE METABOLISM IN THE FED STATE – CLINICAL AND PATHOPHYSIOLOGICAL SIGNIFICANCE

In our recent report, it remained unclear whether or not triglyceride-rich lipoprotein remnants (RLP) were associated with the risk of sudden coronary death in younger cases without coronary atherosclerosis that were detected in about 10% of all sudden coronary death cases in Japan. These cases were categorized as ‘origin unknown, but suspected to be due to coronary spasm’, the so called ‘pokkuri disease’ in Japan. The present study population consisted of 108 sudden death cases without coronary atherosclerosis [(pokkuri disease n=57) and non-cardiac sudden death (control n=51)] aged 20–69 years from Kanagawa prefecture in Japan. All individuals had died suddenly and unexpectedly, most had no significant history of medical conditions including cardiac symptoms and had not taken medications prior to death according to their medical records. All the autopsies were performed within 12 h after death. Plasma total cholesterol (TC), triglycerides (TG), phospholipids, RLP-C and RLP-TG, VLDL-C, LDL-C, HDL-C, apolipoproteins A-I, A-II, B, C-II, C-III, E, Lp (a) and homocysteine were measured in postmortem plasma samples. The TG-rich lipoprotein remnants measured as RLP-C and RLP-TG were significantly higher in pokkuri disease compared with controls both in fasting and postprandial states (P<0.05 and P<0.001), indicating that RLP-C and RLP-TG were the most significant risk factor in pokkuri disease among the parameters tested in this study. In conclusion the TG level in RLP (RLP-TG) appeared to be strongly associated with the risk of sudden death in the absence of coronary atherosclerosis (pokkuri disease).

Rapid and Simple Profiling of Lipoproteins by Polyacrylamide-Gel Disc Electrophoresis to Determine the Heterogeneity of Low-Density Lipoproteins (LDLs) Including Small, Dense LDL

This study aimed to explore the potential of polyacrylamide-gel disc electrophoresis (PAGE) for lipoprotein profiling in clinical practice. Blood samples were collected from 146 patients with type 2 diabetes mellitus and lipid parameters were assayed by PAGE, including small, dense low-density lipoprotein (LDL) (n = 41), and triglyceride-rich lipoprotein remnant cholesterol (n = 37). We also used a commercial kit to measure small, dense LDL (n = 41). By PAGE, we obtained the percentage of the area under the curve (AUC %) of each peaks and calculated respective AUC% x total cholesterol (AUC%xTC) values. The calculated values of LDL-AUC%xTC, small LDL-AUC%xTC, and HDL-AUC%xTC values were correlated well with values from homogeneous assay for LDL-cholesterol, small, dense LDL-cholesterol, and HDL-cholesterol assays (r = 0.94, 0.81, and 0.89, respectively). PAGE combined with measurement of total cholesterol and triglycerides provides a rapid evaluation of anti- or pro-atherogenic lipoproteins and a simple profiling system for both the "quantity" and "quality" of lipoproteins, allowing a better assessment of the risk of coronary artery diseases. This article discusses several methods for simple and rapid lipid profiling and outlines some recent patents relevant to the methods.

Apolipoprotein CIII and Atherosclerosis

The prevailing concept of mechanisms responsible for the development of atherosclerotic lesions largely focuses on the accumulation and retention of low-density lipoproteins in the arterial intima and their subsequent oxidative modification. This oxidation leads to activation of the endothelium, and particularly, expression of adhesion molecules that mediate leukocyte adherence and chemokines which initiate the inflammation reaction that is widely accepted as being responsible for the development and progression of atherosclerotic lesions.1,2 There is also a strong body of evidence to indicate that elevated triacylglycerides (triglycerides) are an independent risk factor for atherosclerosis.3–5 Article p 731 One mechanism that can contribute to elevated triglycerides involves apolipoprotein CIII (apoCIII). apoCIII is a small protein that resides on the surface of very-low-density lipoproteins (VLDLs), low-density lipoproteins, chylomicrons, and high-density lipoproteins (Figure). It exists as multiple species, as either a nonglycosylated isoform (apoCIIIo) or a glycosylated isoform (apoCIII1 or apoCIII2); all three isoforms have similar plasma half-lives and probably have very similar physiological functions. Increased apoCIII production is a characteristic feature of patients with hypertriglyceridemia,6 and plasma apoCIII levels have been positively correlated with plasma triacylglycerol concentrations and also have been associated with severity of hypertriglyceridemia.7 Elevated plasma apoCIII concentration and, specifically, accumulation of apoCIII in triacylglycerol-rich lipoproteins is casually related to hypertriglyceridemia in patients with metabolic syndrome and has also been associated with insulin resistance.8 apoCIII is a major regulator of lipolysis, as it noncompetitively inhibits endothelial-bound lipoprotein lipase, the enzyme that hydrolyzes triacylglycerols in …