Síndrome de quilomicronemia familiar: primer caso reportado en Ecuador / Familial chylomicronemia syndrome: The first case reported in Ecuador

El síndrome de quilomicronemia familiar (SQF) es una entidad genética de herencia autosómica recesiva. Las mutaciones en genes (como APOC2, APOAV, LMF-1, GPIHBP-1) que codifican para proteínas que regulan la maduración, transporte o polimerización de lipoproteína lipasa-1 son las causas más comunes, pero no las únicas. El objetivo de este estudio fue reportar el primer caso documentado en el Ecuador.Caso clínico: hombre de 38 años que presentó hepatoesplenomegalia crónica, trombocitopenia, atrofia pancreática e hipertrigliceridemia severa refractaria al tratamiento. Se realizó un análisis molecular por secuenciación de nueva generación que determinó una deficiencia de lipoproteína lipasa OMIM #238600 en homocigosis. La confirmación genética es necesaria a fin de poder establecer la etiología de HTGS para un adecuado manejo de esta patología.(AU)

Familial chylomicronemia syndrome (FCS) is a genetic entity with autosomal recessive inheritance. Mutations in genes (such as APOC2, APOAV, LMF-1, GPIHBP-1) that code for proteins that regulate the maturation, transport, or polymerization of lipoprotein lipase-1 are the most common causes, but not the only ones. The objective of this study was to report the first documented case in Ecuador.Clinical caseA 38-year-old man presented with chronic hepatosplenomegaly, thrombocytopenia, pancreatic atrophy, and severe hypertriglyceridemia refractory to treatment. A molecular analysis was performed by next generation sequencing that determined a deficiency of Lipoprotein Lipase OMIM #238600 in homozygosis. Genetic confirmation is necessary in order to establish the etiology of HTGS for an adequate management of this pathology.(AU)

Physiological Bases for the Superiority of Apolipoprotein B Over Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol as a Marker of Cardiovascular Risk.

In 2019, the European Society of Cardiology/European Atherosclerosis Society stated that apolipoprotein B (apoB) was a more accurate marker of cardiovascular risk than low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol. Since then, the evidence has continued to mount in favor of apoB. This review explicates the physiological mechanisms responsible for the superiority of apoB as a marker of the cardiovascular risk attributable to the atherogenic apoB lipoprotein particles chylomicron remnants, very low-density lipoprotein, and low-density lipoprotein particles. First, the nature and relative numbers of these different apoB particles will be outlined. This will make clear why low-density lipoprotein particles are almost always the major determinants of cardiovascular risk and why the concentrations of triglycerides and LDL-C may obscure this relation. Next, the mechanisms that govern the number of very low-density lipoprotein and low-density lipoprotein particles will be outlined because, except for dysbetalipoproteinemia, the total number of apoB particles determines cardiovascular risk, Then, the mechanisms that govern the cholesterol mass within very low-density lipoprotein and low-density lipoprotein particles will be reviewed because these are responsible for the discordance between the mass of cholesterol within apoB particles, measured either as LDL-C or non-high-density lipoprotein cholesterol, and the number of apoB particles measured as apoB, which creates the superior predictive power of apoB over LDL-C and non-high-density lipoprotein cholesterol. Finally, the major apoB dyslipoproteinemias will be briefly outlined. Our objective is to provide a physiological framework for health care givers to understand why apoB is a more accurate marker of cardiovascular risk than LDL-C or non-high-density lipoprotein cholesterol.

Intestinal lipid absorption and transport in type 2 diabetes.

Postprandial hyperlipidaemia is an important feature of diabetic dyslipidaemia and plays an important role in the development of cardiovascular disease in individuals with type 2 diabetes. Postprandial hyperlipidaemia in type 2 diabetes is secondary to increased chylomicron production by the enterocytes and delayed catabolism of chylomicrons and chylomicron remnants. Insulin and some intestinal hormones (e.g. glucagon-like peptide-1 [GLP-1]) influence intestinal lipid metabolism. In individuals with type 2 diabetes, insulin resistance and possibly reduced GLP-1 secretion are involved in the pathophysiology of postprandial hyperlipidaemia. Several factors are involved in the overproduction of chylomicrons: (1) increased expression of microsomal triglyceride transfer protein, which is a key enzyme in chylomicron synthesis; (2) higher stability and availability of apolipoprotein B-48; and (3) increased de novo lipogenesis. Individuals with type 2 diabetes present with disorders of cholesterol metabolism in the enterocytes with reduced absorption and increased synthesis. The increased production of chylomicrons in type 2 diabetes is also associated with a reduction in their catabolism, mostly because of a reduction in activity of lipoprotein lipase. Modification of the microbiota, which is observed in type 2 diabetes, may also generate disorders of intestinal lipid metabolism, but human data remain limited. Some glucose-lowering treatments significantly influence intestinal lipid absorption and transport. Postprandial hyperlipidaemia is reduced by metformin, pioglitazone, alpha-glucosidase inhibitors, dipeptidyl peptidase 4 inhibitors and GLP-1 agonists. The most pronounced effect is observed with GLP-1 agonists, which reduce chylomicron production significantly in individuals with type 2 diabetes and have a direct effect on the intestine by reducing the expression of genes involved in intestinal lipoprotein metabolism. The effect of sodium-glucose cotransporter 2 inhibitors on intestinal lipid metabolism needs to be clarified.

High remnant cholesterol level is relevant to diabetic retinopathy in type 2 diabetes mellitus.

BACKGROUND: Diabetic retinopathy (DR) is the primary oculopathy causing blindness in diabetic patients. Currently, there is increasing interest in the role of lipids in the development of diabetic retinopathy, but it remains controversial. Remnant cholesterol (RC) is an inexpensive and easily measurable lipid parameter; however, the relationship between RC and DR in type 2 diabetes mellitus (T2DM) has not been elucidated. This research investigates the relevance between RC levels and DR severity while building a risk prediction model about DR. METHODS: In this single-centre retrospective cross-sectional study. Each hospitalised T2DM patient had no oral lipid-lowering drugs in the past three months, and coronary angiography showed epicardial coronary artery stenosis of less than 50% and completed seven-field stereo photographs, fluorescein fundus angiography, and optical coherence tomography detection. The RC value is calculated according to the internationally recognised formula. Binary logistic regression was used to correct confounding factors, and the receiver operating characteristic (ROC) analysis was used to identify risk factors and assess the nomogram's diagnostic efficiency. RESULTS: A total of 456 T2DM patients were included in the study. The RC levels in the DR team was higher [0.74 (0.60-1.12) mmo/l vs 0.54 (0.31-0.83) mmol/l P < 0.001] in the non-DR team. After adjusting for confounding elements, RC levels are still associated with DR risk (OR = 5.623 95%CI: 2.996-10.556 P < 0.001). The ratio of DR in every stage (except mild non-proliferative diabetic retinopathy) and DME in the high RC level team were further increased compared to the low-level team (all P < 0.001). After ROC analysis, the overall risk of DR was predicted by a nomogram constructed for RC, diabetes duration, and the neutrophil-lymphocyte ratio as 0.758 (95%CI 0.714-0.802 P < 0.001). CONCLUSIONS: High RC levels may be a potential risk factor for diabetic retinopathy, and the nomogram does better predict DR. Despite these essential findings, the limitation of this study is that it is single-centred and small sample size analysis.

Lean adolescents with insulin resistance display higher angiopoietin like protein 3, ApoC-III and chylomicron remnant dyslipidemia.

BACKGROUND: Triglyceride-rich lipoproteins (TRL: chylomicrons and VLDL) are a key component of diabetes dyslipoproteinemia and cardiovascular risk. We have shown that it is already prevalent in obese adolescents in association with lipoprotein lipase (LPL) dysregulation. Insulin resistance (IR) suffices to produce TRL dyslipoproteinemia and LPL dysfunction even in the absence of obesity. METHODS: This cross-sectional study included euglycemic adolescents between 15 and 19 y, classified in 4 groups according to BMI, HOMA-IR and fasting lipid as: metabolically healthy lean (MHL, n = 30), metabolically unhealthy lean (MUL, n = 25), metabolically healthy obese (MHO, = 30), and metabolically unhealthy obese (MUO, n = 42). RESULTS: As compared to MHL, MUL participants showed 73% higher concentrations of ApoB-48; 84% of ApoC-III; 24% ANGPTL-3; 200% of TG; 218% of VLDL-C and 238% of TG/HDL-C c, No changes were found in LPL mass. Interestingly, the differences in these parameters between MUL and MHO were not significant. CONCLUSION: Euglycemic lean adolescents with IR display TRL dyslipoproteinemia with increased inhibition of LPL as highlighted by higher concentrations of ANGPTL-3, ApoC-III and fasting chylomicron remnants (ApoB-48).

Association of remnant cholesterol with nonalcoholic fatty liver disease: a general population-based study.

BACKGROUND: Remnant cholesterol (RC) mediates the progression of coronary artery disease, diabetic complications, hypertension, and chronic kidney disease. Limited information is available on the association of RC with nonalcoholic fatty liver disease (NAFLD). This study aimed to explore whether RC can be used to independently evaluate the risk of NAFLD in the general population and to analyze the predictive value of RC for NAFLD. METHODS: The study included 14,251 subjects enrolled in a health screening program. NAFLD was diagnosed by ultrasound, and the association of RC with NAFLD was assessed using the receiver operating characteristic (ROC) curve and logistic regression equation. RESULTS: Subjects with elevated RC had a significantly higher risk of developing NAFLD after fully adjusting for potential confounding factors (OR 1.77 per SD increase, 95% CI 1.64-1.91, P trend< 0.001). There were significant differences in this association among sex, BMI and age stratification. Compared with men, women were facing a higher risk of RC-related NAFLD. Compared with people with normal BMI, overweight and obesity, the risk of RC-related NAFLD was higher in thin people. In different age stratifications, when RC increased, young people had a higher risk of developing NAFLD than other age groups. Additionally, ROC analysis results showed that among all lipid parameters, the AUC of RC was the largest (women: 0.81; men: 0.74), and the best threshold for predicting NAFLD was 0.54 in women and 0.63 in men. CONCLUSIONS: The results obtained from this study indicate that (1) in the general population, RC is independently associated with NAFLD but not with other risk factors. (2) Compared with traditional lipid parameters, RC has a better predictive ability for NAFLD in men.

CREBH normalizes dyslipidemia and halts atherosclerosis in diabetes by decreasing circulating remnant lipoproteins.

Loss-of-function mutations in the transcription factor CREB3L3 (CREBH) associate with severe hypertriglyceridemia in humans. CREBH is believed to lower plasma triglycerides by augmenting the activity of lipoprotein lipase (LPL). However, by using a mouse model of type 1 diabetes mellitus (T1DM), we found that greater liver expression of active CREBH normalized both elevated plasma triglycerides and cholesterol. Residual triglyceride-rich lipoprotein (TRL) remnants were enriched in apolipoprotein E (APOE) and impoverished in APOC3, an apolipoprotein composition indicative of increased hepatic clearance. The underlying mechanism was independent of LPL, as CREBH reduced both triglycerides and cholesterol in LPL-deficient mice. Instead, APOE was critical for CREBH's ability to lower circulating remnant lipoproteins because it failed to reduce TRL cholesterol in Apoe-/- mice. Importantly, individuals with CREB3L3 loss-of-function mutations exhibited increased levels of remnant lipoproteins that were deprived of APOE. Recent evidence suggests that impaired clearance of TRL remnants promotes cardiovascular disease in patients with T1DM. Consistently, we found that hepatic expression of CREBH prevented the progression of diabetes-accelerated atherosclerosis. Our results support the proposal that CREBH acts through an APOE-dependent pathway to increase hepatic clearance of remnant lipoproteins. They also implicate elevated levels of remnants in the pathogenesis of atherosclerosis in T1DM.

Triglyceride-Rich Lipoprotein Remnants and Cardiovascular Disease.

BACKGROUND: Triglycerides, cholesterol, and their metabolism are linked due to shared packaging and transport within circulating lipoprotein particles. While a case for a causal role of cholesterol-carrying low-density lipoproteins (LDLs) in atherosclerosis is well made, the body of scientific evidence for a causal role of triglyceride-rich lipoproteins (TRLs) is rapidly growing, with multiple lines of evidence (old and new) providing robust support. CONTENT: This review will discuss current perspectives and accumulated evidence that an overabundance of remnant lipoproteins stemming from intravascular remodeling of nascent TRLs-chylomicrons and very low-density lipoproteins (VLDL)-results in a proatherogenic milieu that augments cardiovascular risk. Basic mechanisms of TRL metabolism and clearance will be summarized, assay methods reviewed, and pivotal clinical studies highlighted. SUMMARY: Remnant lipoproteins are rendered highly atherogenic by their high cholesterol content, altered apolipoprotein composition, and physicochemical properties. The aggregate findings from multiple lines of evidence suggest that TRL remnants play a central role in residual cardiovascular risk.

Effects of Evolocumab on the Postprandial Kinetics of Apo (Apolipoprotein) B100- and B48-Containing Lipoproteins in Subjects With Type 2 Diabetes.

OBJECTIVE: Increased risk of atherosclerotic cardiovascular disease in subjects with type 2 diabetes is linked to elevated levels of triglyceride-rich lipoproteins and their remnants. The metabolic effects of PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors on this dyslipidemia were investigated using stable-isotope-labeled tracers. Approach and Results: Triglyceride transport and the metabolism of apos (apolipoproteins) B48, B100, C-III, and E after a fat-rich meal were investigated before and on evolocumab treatment in 13 subjects with type 2 diabetes. Kinetic parameters were determined for the following: apoB48 in chylomicrons; triglyceride in VLDL1 (very low-density lipoprotein) and VLDL2; and apoB100 in VLDL1, VLDL2, IDL (intermediate-density lipoprotein), and LDL (low-density lipoprotein). Evolocumab did not alter the kinetics of apoB48 in chylomicrons or apoB100 or triglyceride in VLDL1. In contrast, the fractional catabolic rates of VLDL2-apoB100 and VLDL2-triglyceride were both increased by about 45%, which led to a 28% fall in the VLDL2 plasma level. LDL-apoB100 was markedly reduced by evolocumab, which was linked to metabolic heterogeneity in this fraction. Evolocumab increased clearance of the more rapidly metabolized LDL by 61% and decreased production of the more slowly cleared LDL by 75%. ApoC-III kinetics were not altered by evolocumab, but the apoE fractional catabolic rates increased by 45% and the apoE plasma level fell by 33%. The apoE fractional catabolic rates was associated with the decrease in VLDL2- and IDL-apoB100 concentrations. CONCLUSIONS: Evolocumab had only minor effects on lipoproteins that are involved in triglyceride transport (chylomicrons and VLDL1) but, in contrast, had a profound impact on lipoproteins that carry cholesterol (VLDL2, IDL, LDL). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02948777.

The longitudinal association of remnant cholesterol with cardiovascular outcomes in patients with diabetes and pre-diabetes.

BACKGROUND: The atherogenicity of remnant cholesterol (RC) has been underlined by recent guidelines, which was linked to coronary artery disease (CAD), especially for patients with diabetes mellitus (DM). This study aimed to examine the prognostic value of plasma RC in the patients with CAD under different glucose metabolism status. METHODS: Fasting plasma RC were directly calculated or measured in 4331 patients with CAD. Patients were followed for the occurrence of major adverse cardiovascular events (MACEs) and categorized according to both glucose metabolism status [DM, pre-DM, normoglycemia (NG)] and RC levels. Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals. RESULTS: During a mean follow-up of 5.1 years, 541 (12.5%) MACEs occurred. The risk for MACEs was significantly higher in patients with elevated RC levels after adjustment for potential confounders. No significant difference in MACEs was observed between pre-DM and NG groups (p > 0.05). When stratified by combined status of glucose metabolism and RC, highest levels of calculated and measured RC were significant and independent predictors of developing MACEs in pre-DM (HR: 1.64 and 1.98; both p < 0.05) and DM (HR: 1.62 and 2.05; both p < 0.05). High RC levels were also positively associated with MACEs in patients with uncontrolled DM. . CONCLUSIONS: In this large-scale and long-term follow-up cohort study, data firstly demonstrated that higher RC levels were significantly associated with the worse prognosis in DM and pre-DM patients with CAD, suggesting that RC may be a target for patients with impaired glucose metabolism.

The VLDL receptor plays a key role in the metabolism of postprandial remnant lipoproteins.

A new concept to account for the process of postprandial remnant lipoprotein metabolism is proposed based on the characteristics of lipoprotein particles and their receptors. The characteristics of remnant lipoprotein (RLP) were investigated using an immuno-separation method. The majority of the postprandial lipoproteins increased after fat intake was shown to be VLDL remnants, not chylomicron (CM) remnants, based on the significantly high ratio of apoB100/apoB48 in the RLP and the high degree of similarity in the particle size of the apoB48 and apoB100 carrying lipoproteins, which fluctuate in parallel during a 6 h period after fat intake. The VLDL receptor was discovered as a receptor for TG-rich lipoprotein metabolism and is located in peripheral tissues such as skeletal muscle, adipose tissue, etc., but not in the liver. Postprandial VLDL particles are strongly bound and internalized into cells expressing the VLDL receptor. Ligands that bind to VLDL receptor, such as LPL and Lp(a), present in RLP. The presence of various specific ligands in VLDL remnants may enhance the capacity for binding to the VLDL receptor, which play the role primarily for energy delivery to the peripheral tissues, but is also a causal factor in atherogenic diseases when excessively and/or continuously remained in plasma.

Ezetimibe in Combination With Simvastatin Reduces Remnant Cholesterol Without Affecting Biliary Lipid Concentrations in Gallstone Patients.

Background In randomized trials (SHARP [Study of Heart and Renal Protection], IMPROVE -IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), combination of statin and ezetimibe resulted in additional reduction of cardiovascular events. The reduction was greater in patients with type 2 diabetes mellitus (T2 DM ), where elevated remnant cholesterol and high cardiovascular disease risk is characteristic. To evaluate possible causes behind these results, 40 patients eligible for cholecystectomy, randomized to simvastatin, ezetimibe, combined treatment (simvastatin+ezetimibe), or placebo treatment during 4 weeks before surgery, were studied. Methods and Results Fasting blood samples were taken before treatment start and at the end (just before surgery). Bile samples and liver biopsies were collected during surgery. Hepatic gene expression levels were assessed with qPCR . Lipoprotein, apolipoprotein levels, and content of cholesterol, cholesteryl ester, and triglycerides were measured after lipoprotein fractionation. Lipoprotein subclasses were analyzed by nuclear magnetic resonance. Apolipoprotein affinity for human arterial proteoglycans ( PG ) was measured. Biomarkers of cholesterol biosynthesis and intestinal absorption and bile lipid composition were analyzed using mass spectrometry. Combined treatment caused a statistically significant decrease in plasma remnant particles and apolipoprotein B (ApoB)/lipoprotein content of cholesterol, cholesteryl esters, and triglycerides. All treatments reduced ApoB-lipoprotein PG binding. Simvastatin and combined treatment modified the composition of lipoproteins. Changes in biomarkers of cholesterol synthesis and absorption and bile acid synthesis were as expected. No adverse events were found. Conclusions Combined treatment caused atheroprotective changes on ApoB-lipoproteins, remnant particles, bile components, and in ApoB-lipoprotein affinity for arterial PG . These effects might explain the decrease of cardiovascular events seen in the SHARP and IMPROVE - IT trials. Clinical Trial Registration URL : www.clinicaltrialsregister.eu . Unique identifier: 2006-004839-30).

Deletion of Lymphangiogenic and Angiogenic Growth Factor VEGF-D Leads to Severe Hyperlipidemia and Delayed Clearance of Chylomicron Remnants.

Objective- Dyslipidemia is one of the key factors behind coronary heart disease. Blood and lymphatic vessels play pivotal roles in both lipoprotein metabolism and development of atherosclerotic plaques. Recent studies have linked members of VEGF (vascular endothelial growth factor) family to lipid metabolism, but the function of VEGF-D has remained unexplored. Here, we investigated how the deletion of VEGF-D affects lipid and lipoprotein metabolism in atherogenic LDLR-/- ApoB100/100 mice. Approach and Results- Deletion of VEGF-D (VEGF-D-/-LDLR-/-ApoB100/100) led to markedly elevated plasma cholesterol and triglyceride levels without an increase in atherogenesis. Size distribution and hepatic lipid uptake studies confirmed a delayed clearance of large chylomicron remnant particles that cannot easily penetrate through the vascular endothelium. Mechanistically, the inhibition of VEGF-D signaling significantly decreased the hepatic expression of SDC1 (syndecan 1), which is one of the main receptors for chylomicron remnant uptake when LDLR is absent. Immunohistochemical staining confirmed reduced expression of SDC1 in the sinusoidal surface of hepatocytes in VEGF-D deficient mice. Furthermore, hepatic RNA-sequencing revealed that VEGF-D is also an important regulator of genes related to lipid metabolism and inflammation. The lack of VEGF-D signaling via VEGFR3 (VEGF receptor 3) led to lowered expression of genes regulating triglyceride and cholesterol production, as well as downregulation of peroxisomal ß-oxidation pathway. Conclusions- These results demonstrate that VEGF-D, a powerful lymphangiogenic and angiogenic growth factor, is also a major regulator of chylomicron metabolism in mice.

Postprandial remnant lipoproteins as targets for the prevention of atherosclerosis.

PURPOSE OF REVIEW: Oxidized low-density lipoprotein (Ox-LDL) and chylomicron remnants were previously proposed as the most atherogenic lipoproteins for the causal lipoproteins of atherosclerosis. However, there are still controversies on these hypothesizes. Therefore, we have proposed a new hypothesis based on our recent findings of remnant lipoproteins (RLPs) in postprandial plasma. RECENT FINDINGS: Plasma RLP-C and RLP-TG increased significantly after fat load. More than 80% of the increased triglycerides after fat load consisted of the triglycerides in RLP, which contained greater amount of apoB100 than apoB48 particles as mostly very low density lipoproteins (VLDL) remnants. The majority of lipoprotein lipase (LPL) in plasma was found in RLP as RLP-LPL complex, which is released into circulation after hydrolysis. LPL activity and concentration in plasma did not increase after food intake associated with the insufficient hydrolysis of chylomicrons and VLDL and resulted in the significant increase of RLP-TG. Plasma LPL was inversely correlated with RLP particle size and number. SUMMARY: VLDL remnants have been shown as the major atherogenic lipoproteins in postprandial plasma associated with LPL activity as the targets for prevention of atherosclerosis. We also proposed a new definition of RLPs, 'LPL bound TG-rich lipoproteins' based on the findings of RLP-LPL complex.

APOC3 Loss-of-Function Mutations, Remnant Cholesterol, Low-Density Lipoprotein Cholesterol, and Cardiovascular Risk: Mediation- and Meta-Analyses of 137 895 Individuals.

OBJECTIVE: Loss-of-function mutations in APOC3 associate with low remnant cholesterol levels and low risk of ischemic vascular disease (IVD). Because some studies show an additional association with low levels of low-density lipoprotein cholesterol (LDL-C), low LDL-C may explain the low risk of IVD in APOC3 loss-of-function heterozygotes. We tested to what extent the low risk of IVD in APOC3 loss-of-function heterozygotes is mediated by low plasma remnant cholesterol and LDL-C. APPROACH AND RESULTS: In APOC3 loss-of-function heterozygotes versus noncarriers, we first determined remnant cholesterol and LDL-C levels in meta-analyses of 137 895 individuals. Second, we determined whether the association with LDL-C was masked by lipid-lowering therapy. Finally, using mediation analysis, we determined the fraction of the low risk of IVD and ischemic heart disease mediated by remnant cholesterol and LDL-C. In meta-analyses, remnant cholesterol was 43% lower (95% confidence interval, 40%-47%), and LDL-C was 4% lower (1%-6%) in loss-of-function heterozygotes (n=776) versus noncarriers. In the general population, LDL-C was 3% lower in loss-of-function heterozygotes versus noncarriers, 4% lower when correcting for lipid-lowering therapy, and 3% lower in untreated individuals (P values, 0.06-0.008). Remnant cholesterol mediated 37% of the observed 41% lower risk of IVD and 54% of the observed 36% lower risk of ischemic heart disease; corresponding values mediated by LDL-C were 1% and 2%. CONCLUSIONS: The low risk of IVD observed in APOC3 loss-of-function heterozygotes is mainly mediated by the associated low remnant cholesterol and not by low LDL-C. Furthermore, the contribution of LDL-C to IVD risk was not masked by lipid-lowering therapy. This suggests APOC3 and remnant cholesterol as important new targets for reducing cardiovascular risk.

Evidence for increased chylomicron remnants in rheumatoid arthritis.

BACKGROUND: Levels of apolipoprotein (apo) B48 may be increased in conditions associated with systemic inflammation and increased cardiovascular disease (CVD) risk such as rheumatoid arthritis (RA). We aimed to evaluate apo B48 levels in patients with RA in relation to subclinical atherosclerosis. METHODS: Patients with RA (without CVD) and controls without RA but with high CVD risk (based on the presence of diabetes mellitus or a history of CVD) and healthy controls were included in this cross-sectional study. Carotid intima-media thickness (cIMT) was measured as a surrogate for vascular damage. RESULTS: In total, 312 patients with RA, 65 controls with high CVD risk and 36 healthy controls were included. Patients with RA had the highest mean apo B48 (10.00 ± 6.65 mg/L) compared to controls with high CVD risk and healthy controls (8.37 ± 5.16 and 5.22 ± 2.46, P < .001). Triglycerides levels were comparable with controls. In RA, apo B48 correlated positively with triglycerides (r = .645; P < .001) but not with cIMT. However, in RA subjects not using lipid or blood pressure lowering medication, a weak correlation was found with cIMT (r = .157; P = .014). RA patients in the highest apo B48 tertile were more often rheumatoid factor positive and anti-CCP positive compared to the lowest tertile. CONCLUSION: Rheumatoid arthritis patients have higher levels of apo B48 compared to controls with high CVD risk and healthy controls, with normal levels of triglycerides. This accumulation of atherogenic chylomicron remnants may contribute to the elevated CVD risk in RA patients.

Suppression of Hepatic FLOT1 (Flotillin-1) by Type 2 Diabetes Mellitus Impairs the Disposal of Remnant Lipoproteins via Syndecan-1.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) and the atherometabolic syndrome exhibit a deadly dyslipoproteinemia that arises in part from impaired hepatic disposal of C-TRLs (cholesterol- and triglyceride-rich remnant apoB [apolipoprotein B] lipoproteins). We previously identified syndecan-1 as a receptor for C-TRLs that directly mediates endocytosis via rafts, independent from coated pits. Caveolins and flotillins form rafts but facilitate distinct endocytotic pathways. We now investigated their participation in syndecan-1-mediated disposal of C-TRLs and their expression in T2DM liver. APPROACH AND RESULTS: In cultured liver cells and nondiabetic murine livers, we found that syndecan-1 coimmunoprecipitates with FLOT1 (flotillin-1) but not with CAV1 (caveolin-1). Binding of C-TRLs to syndecan-1 on the surface of liver cells enhanced syndecan-1/FLOT1 association. The 2 molecules then trafficked together into the lysosomes, implying limited if any recycling back to the cell surface. The interaction requires the transmembrane/cytoplasmic region of syndecan-1 and the N-terminal hydrophobic domain of FLOT1. Knockdown of FLOT1 in cultured liver cells substantially inhibited syndecan-1 endocytosis. Livers from obese, T2DM KKAy mice exhibited 60% to 70% less FLOT1 protein and mRNA than in nondiabetic KK livers. An adenoviral construct to enhance hepatic expression of wild-type FLOT1 in T2DM mice normalized plasma triglycerides, whereas a mutant FLOT1 missing its N-terminal hydrophobic domain had no effect. Moreover, the adenoviral vector for wild-type FLOT1 lowered plasma triglyceride excursions and normalized retinyl excursions in T2DM KKAy mice after a corn oil gavage, without affecting postprandial production of C-TRLs. CONCLUSIONS: FLOT1 is a novel participant in the disposal of harmful C-TRLs via syndecan-1. Low expression of FLOT1 in T2DM liver may contribute to metabolic dyslipoproteinemia.

The LDL Receptor-Related Protein 1: At the Crossroads of Lipoprotein Metabolism and Insulin Signaling.

The metabolic syndrome is an escalating worldwide public health concern. Defined by a combination of physiological, metabolic, and biochemical factors, the metabolic syndrome is used as a clinical guideline to identify individuals with a higher risk for type 2 diabetes and cardiovascular disease. Although risk factors for type 2 diabetes and cardiovascular disease have been known for decades, the molecular mechanisms involved in the pathophysiology of these diseases and their interrelationship remain unclear. The LDL receptor-related protein 1 (LRP1) is a large endocytic and signaling receptor that is widely expressed in several tissues. As a member of the LDL receptor family, LRP1 is involved in the clearance of chylomicron remnants from the circulation and has been demonstrated to be atheroprotective. Recently, studies have shown that LRP1 is involved in insulin receptor trafficking and regulation and glucose metabolism. This review summarizes the role of tissue-specific LRP1 in insulin signaling and its potential role as a link between lipoprotein and glucose metabolism in diabetes.