Chylomicron Clearance Research Articles

Effects of Age and Diet on Triglyceride Metabolism in Mice.

Both age and diet can contribute to alterations in triglyceride metabolism and subsequent metabolic disease. In humans, plasma triglyceride levels increase with age. Diets high in saturated fats can increase triglyceride levels while diets high in omega-3 fatty acids decrease triglyceride levels. Here we asked how age and long-term diet effected triglyceride metabolism in mice. We fed male and female mice a low-fat diet, a western diet, or a diet high in polyunsaturated and omega-3 (n-3) fatty acids for up to 2 years. We measured survival, body composition, plasma triglyceride levels, chylomicron clearance, and oral fat, glucose, and insulin tolerance. Triglyceride levels in mice did not increase with age, regardless of diet. Oral fat tolerance increased with age, while chylomicron clearance remained unchanged. Mice fed western diet had decreased survival. Interestingly, mice fed the n-3 diet gained more lean mass, and had lower insulin levels than mice fed either low-fat or western diet. Moreover, triglyceride uptake into the hearts of mice fed the n-3 diet was strikingly higher than in other groups. In mice, age-induced changes in triglyceride metabolism did not match those in humans. Our data suggested that mice, like humans, had decreased fat absorption with age, but plasma triglyceride clearance did not decrease with age in mice, resulting in lower plasma triglyceride levels and improved oral fat tolerance with age. A chronic diet high in n-3 fatty acids increased insulin sensitivity and uptake of triglycerides specifically into the heart but how these observations are connected is unclear.

A Systematic Review on the Impact of Cholesterol Levels on Diabetes Mellitus

Diabetes mellitus (DM) is a common metabolic disorder characterized by defects in insulin secretion and action, or both, resulting in chronic hyperglycemia and altered metabolism of carbohydrates, fats, and proteins. In the absence of the major risk factors, diabetes is associated with increased morbidity and mortality from cardiovascular disease. The prevalence of diabetes is 10.1 crores, as per the Indian Council of Medical Research – India Diabetes (ICMR INDIAB) study published in 2023. Serum lipid abnormalities (dyslipidemia) are commonly seen in diabetic populations, irrespective of insulin deficiency or insulin resistance. When insulin activity is very low, it severely inhibits lipoprotein lipase production, which significantly impairs the digestion of triglyceride-rich lipoproteins. As a result, there is an increase in triglyceride-rich lipoproteins and a delay in the clearance of chylomicrons and VLDL. Additionally, insulinopenia leads to a substantial increase in lipolysis in adipose tissue, causing the release of free fatty acids into the bloodstream. This higher supply of fatty acids to the liver improves triglyceride synthesis in the liver, ultimately resulting in increased production and secretion of VLDL. By lowering serum cholesterol with statins, which inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis, decreases the risk of CHD.

Contribution of intestinal triglyceride-rich lipoproteins to residual atherosclerotic cardiovascular disease risk in individuals with type 2 diabetes on statin therapy

Aims/hypothesisThis study explored the hypothesis that significant abnormalities in the metabolism of intestinally derived lipoproteins are present in individuals with type 2 diabetes on statin therapy. These abnormalities may contribute to residual CVD risk.MethodsTo investigate the kinetics of ApoB-48- and ApoB-100-containing lipoproteins, we performed a secondary analysis of 11 overweight/obese individuals with type 2 diabetes who were treated with lifestyle counselling and on a stable dose of metformin who were from an earlier clinical study, and compared these with 11 control participants frequency-matched for age, BMI and sex. Participants in both groups were on a similar statin regimen during the study. Stable isotope tracers were used to determine the kinetics of the following in response to a standard fat-rich meal: (1) apolipoprotein (Apo)B-48 in chylomicrons and VLDL; (2) ApoB-100 in VLDL, intermediate-density lipoprotein (IDL) and LDL; and (3) triglyceride (TG) in VLDL.ResultsThe fasting lipid profile did not differ significantly between the two groups. Compared with control participants, in individuals with type 2 diabetes, chylomicron TG and ApoB-48 levels exhibited an approximately twofold higher response to the fat-rich meal, and a twofold higher increment was observed in ApoB-48 particles in the VLDL1 and VLDL2 density ranges (all p < 0.05). Again comparing control participants with individuals with type 2 diabetes, in the latter, total ApoB-48 production was 25% higher (556 ± 57 vs 446 ± 57 mg/day; p < 0.001), conversion (fractional transfer rate) of chylomicrons to VLDL was around 40% lower (35 ± 25 vs 82 ± 58 pools/day; p=0.034) and direct clearance of chylomicrons was 5.6-fold higher (5.6 ± 2.2 vs 1.0 ± 1.8 pools/day; p < 0.001). During the postprandial period, ApoB-48 particles accounted for a higher proportion of total VLDL in individuals with type 2 diabetes (44%) compared with control participants (25%), and these ApoB-48 VLDL particles exhibited a fivefold longer residence time in the circulation (p < 0.01). No between-group differences were seen in the kinetics of ApoB-100 and TG in VLDL, or in LDL ApoB-100 production, pool size and clearance rate. As compared with control participants, the IDL ApoB-100 pool in individuals with type 2 diabetes was higher due to increased conversion from VLDL2.Conclusions/interpretationAbnormalities in the metabolism of intestinally derived ApoB-48-containing lipoproteins in individuals with type 2 diabetes on statins may help to explain the residual risk of CVD and may be suitable targets for interventions.Trial registrationClinicalTrials.gov NCT02948777.Graphical

Post prandial metabolism of lipoproteins in familial chylomicronemia patients treated with lomitapide and tiparvovec

Background and Aims : Familial chylomicronemia syndrome (FCS) is a rare recessive monogenic disease characterized by triglycerides (TG) levels >10 mmol/L. FCS is causally associated with mutations in candidate genes but most patients have mutations in lipoprotein lipase (LPL). Defects in LPL result in reduced clearance of chylomicrons (CM) and development of acute pancreatitis. Treatment of FSC patients is based on combined action of a lipid- and carbohydrate-reduced diet in addition to available hypolipidemic therapies that often fails to achieve a desired TG levels.

Unique Case of Management of Severe Hypertriglyceridemia Secondary to Familial Chylomicronemia Syndrome

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> We review a case of a 61-year-old female diagnosed at age 21 with severe hypertriglyceridemia with debilitating, recurrent episodes of acute pancreatitis. <h3>Objective/Purpose</h3> To review a clinical scenario involving severe hypertriglyceridemia and the role of novel therapies in management. <h3>Methods</h3> Clinical management at tertiary care lipid program. <h3>Results</h3> A 61-year-old slightly overweight female with a history of congenital aplasia of the pancreas, coronary artery disease post stents, pre-diabetes, and non-alcoholic fatty liver disease was diagnosed with severe hypertriglyceridemia secondary to chylomicronemia syndrome at age 21. No secondary causes were identified. She was trialed on several cholesterol and triglyceride lowering medications including niacin, rosuvastatin, gemfibrozil, fenofibrate, fish oil supplements with minimal improvement in symptoms and/or reduction in recurrent hospitalizations for acute pancreatitis. Interestingly, she showed a dramatic ∼70% reduction in triglycerides on evinacumab based on compassionate use, resulting in significant improvement in quality of life with no episodes of acute pancreatitis while on therapy for 12 months. <h3>Conclusions</h3> Familial chylomicronemia syndrome (FCS) is an autosomal recessive disorder with a lack of lipoprotein lipase (LPL) functionality, thereby markedly impairing clearance of chylomicrons from the plasma. The primary reason for concern is an increased risk of acute pancreatitis with an estimated odds ratio of 360 in patients with FCS. Acute pancreatitis, in fact, is responsible for a significant economic burden in the United States with an estimated annual cost of care of over $2 billion, accounting for about 50% higher healthcare-related costs compared to patients without acute pancreatitis. Additionally, studies have shown that patients on statin with high residual cardiovascular risk as well as high triglycerides had higher risk for nonfatal myocardial infarction and nonfatal stroke compared to patients with normal triglycerides. Unfortunately, there are currently no FDA-approved treatments for FCS. For this reason, novel therapies are crucially needed to relieve the debilitating state of these patients. One such concept is the use of ANGPTL3 inhibitor, evinacumab, currently FDA approved for homozygous familial hypercholesterolemia. ANGPTL3 inhibition enhances the activities of endothelial lipase and lipoprotein lipase, thereby reducing levels of LDL-C independent of LDL receptor activity, HDL and triglycerides. Based on meta-analysis and a few Phase 1-2 trials, evinacumab is shown to reduce triglycerides from 50% to 80% in patients with severe hypertriglyceridemia. In our patient, with TG/TC ratio >8:1 and normal to low apoB, FCS is more likely the culprit for severe triglyceride burden, contributing to recurrent acute pancreatitis. Furthermore, our patient also suffers from mixed dyslipidemia and metabolic syndrome, which significantly raises her lifetime atherosclerotic cardiovascular risk. Thus, we propose the use of evinacumab in such patients to not only target high triglycerides to reduce risk of acute pancreatitis but also optimize overall cardiovascular risk.

TMT-Based Plasma Proteomics Reveals Dyslipidemia Among Lowlanders During Prolonged Stay at High Altitudes.

Acute exposure to high altitude perturbs physiological parameters and induces an array of molecular changes in healthy lowlanders. However, activation of compensatory mechanisms and biological processes facilitates high altitude acclimatization. A large number of lowlanders stay at high altitude regions from weeks to months for work and professional commitments, and thus are vulnerable to altitude-associated disorders. Despite this, there is a scarcity of information for molecular changes associated with long-term stay at high altitudes. In the present study, we evaluated oxygen saturation (SpO2), heart rate (HR), and systolic and diastolic blood pressure (SBP and DBP) of lowlanders after short- (7 days, HA-D7) and long-term (3 months, HA-D150) stay at high altitudes, and used TMT-based proteomics studies to decipher plasma proteome alterations. We observed improvements in SpO2 levels after prolonged stay, while HR, SBP, and DBP remained elevated as compared with short-term stay. Plasma proteomics studies revealed higher levels of apolipoproteins APOB, APOCI, APOCIII, APOE, and APOL, and carbonic anhydrases (CA1 and CA2) during hypoxia exposure. Biological network analysis also identified profound alterations in lipoprotein-associated pathways like plasma lipoprotein assembly, VLDL clearance, chylomicron assembly, chylomicron remodeling, plasma lipoprotein clearance, and chylomicron clearance. In corroboration, lipid profiling revealed higher levels of total cholesterol (TC), triglycerides (TGs), low-density lipoprotein (LDL) for HA-D150 whereas high density lipoproteins (HDL) levels were lower as compared with HA-D7 and sea-level indicating dyslipidemia. We also observed higher levels of proinflammatory cytokines IL-6, TNFα, and CRP for HA-D150 along with oxidized LDL (oxLDL), suggesting vascular inflammation and proartherogenic propensity. These results demonstrate that long-term stay at high altitudes exacerbates dyslipidemia and associated disorders.

Familial Partial Lipodystrophy: A Case Study and Review of Recent Literature

Introduction: Familial partial lipodystrophy (FPLD) is a rare genetic disorder characterized by loss of subcutaneous adipose tissue, mainly from the extremities and gluteal region. FPLD is associated with a variety of metabolic abnormalities including severe hypertriglyceridemia (HTG), insulin resistance (IR), and hepatic steatosis. We present a case of FPLD and summarize recent literature on the metabolic features and their management in patients with this rare disease. Case: A 44 year old female with medical history of Type 2 DM, hypertension, hypothyroidism and recurrent pancreatitis from severe HTG was referred to our clinic. She was diagnosed with Type 2 DM in her 30s. Over the ensuing years she had significant IR requiring increasing doses of concentrated insulin (up to 250 units/day). She reported progressive loss of subcutaneous fat from extremities in the preceding 2–3 years. She had recurrent pancreatitis, including a recent hospitalization with TG>8000 mg/dL. On examination, she had typical features of FPLD including loss of subcutaneous adipose tissue from upper and lower extremities including gluteal region, visible skeletal muscles and veins in the extremities, and neck and truncal obesity (Fig. 1). Family history was significant for similar physical and metabolic manifestations in her father and brother. For HTG, she is treated with fibrates and high intensity statin. We avoided the use of fish oil in the patient, because she did not feel well when she was previously on this. Results of the genetic testing are pending. Discussion: FPLD is rare, predominantly autosomal dominant, disorder characterized phenotypically by variable loss of subcutaneous fat and metabolically by severe HTG and insulin resistance. The severity of metabolic derangements is proportional to the degree of the lipodystrophy. The proposed mechanism is limited capacity of adipose tissue to store fat leading to ectopic fat deposition, lipotoxicity and vascular inflammation. Diagnosis is often clinical, especially the loss of subcutaneous fat in the extremities and signs of IR, and is confirmed by genetic testing. Dunnigan syndrome is the most common type of FPLD, which occurs from an autosomal dominant missense mutation in lamin A/C (LMNA). Gene mutations encoding for PPAR-gamma, Akt2, CIDEC, perilipin and the ZMPSTE 24 enzyme are much less common. Treatment of FPLD is challenging, and mostly focuses on managing the metabolic abnormalities. Recent evidence suggests that fish oil may in fact worsen HTG when the main defect driving increased TG is impaired chylomicron clearance, which our patient had on lipid NMR profile. Metreleptin, a human leptin analog, has recently been approved for the management of FPLD with evidence of improved metabolic abnormalities. Recent data also suggests that GLP1 agonists and SGLT2 inhibitors improved glycemic control and reduced daily insulin requirements.

Effects of liraglutide on the metabolism of triglyceride-rich lipoproteins in type 2 diabetes.

To elucidate the impact of liraglutide on the kinetics of apolipoprotein (apo)B48- and apoB100-containing triglyceride-rich lipoproteins in subjects with type 2 diabetes (T2D) after a single fat-rich meal. Subjects with T2D were included in a study to investigate postprandial apoB48 and apoB100 metabolism before and after 16 weeks on l.8 mg/day liraglutide (n = 14) or placebo (n = 4). Stable isotope tracer and compartmental modelling techniques were used to determine the impact of liraglutide on chylomicron and very low-density lipoprotein (VLDL) production and clearance after a single fat-rich meal. Liraglutide reduced apoB48 synthesis in chylomicrons by 60% (p < .0001) and increased the triglyceride/apoB48 ratio (i.e. the size) of chylomicrons (p < .001). Direct clearance of chylomicrons, a quantitatively significant pathway pretreatment, decreased by 90% on liraglutide (p < .001). Liraglutide also reduced VLDL1 -triglyceride secretion (p = .017) in parallel with reduced liver fat. Chylomicron-apoB48 production and particle size were related to insulin sensitivity (p = .015 and p < .001, respectively), but these associations were perturbed by liraglutide. In a physiologically relevant setting that mirrored regular feeding in subjects with T2D, liraglutide promoted potentially beneficial changes on postprandial apoB48 metabolism. Using our data in an integrated metabolic model, we describe how the action of liraglutide in T2D on chylomicron and VLDL kinetics could lead to decreased generation of remnant lipoproteins.

Volanesorsen in the Treatment of Familial Chylomicronemia Syndrome or Hypertriglyceridaemia: Design, Development and Place in Therapy.

Severe hypertriglyceridaemia is associated with pancreatitis and chronic pancreatitis-induced diabetes. Familial chylomicronaemia syndrome (FCS) is a rare autosomal recessive disorder of lipid metabolism characterised by high levels of triglycerides (TGs) due to failure of chylomicron clearance. It causes repeated episodes of severe abdominal pain, fatigue and attacks of acute pancreatitis. There are few current options for its long-term management. The only universal long-term therapy is restriction of total dietary fat intake to <10-15% of daily calories (15 to 20g per day). Many patients have been treated with fibrates and statins with a variable response, but many remain susceptible to pancreatitis. Other genetic syndromes associated with hypertriglyceridaemia include familial partial lipodystrophy (FPLD). Targeting apolipoprotein C3 (apoC3) offers the ability to increase clearance of chylomicrons and other triglyceride-rich lipoproteins. Volanesorsen is an antisense oligonucleotide (ASO) inhibitor of apoC3, which reduces TG levels by 70–80% which has been shown also to reduce rates of pancreatitis and improve well-being in FCS and reduce TGs and improve insulin resistance in FPLD. It is now undergoing licensing and payer reviews. Further developments of antisense technology including small interfering RNA therapy to apoC3 as well as other approaches to modulating triglycerides are in development for this rare disorder.

Effects of gastric bypass surgery on postprandial gut and systemic lipid handling

Obesity is often associated with increased postprandial triglyceride (TG) concentrations, mainly from chylomicrons- and VLDL-TG. These alterations are usually reverted to normal after gastric bypass surgery (GB), through mechanisms which remain unknown. The objective of this study was therefore to assess the contribution of exogenous labelled fatty acids ingested with a meal to postprandial blood chylomicrons and VLDL-TG concentrations after GB. 7GB patients 3-5 years after surgery (GB: 2M/5F, mean BMI 30±2kg/m2, mean age 40±3 years), 6 overweight non operated subjects (OW: 1M/5F, mean BMI 31±3kg/m2, mean age 38±2 years) and 8 normal weight healthy subjects (NW: 4M/4F, mean BMI 22±1kg/m2, mean age 26±4 years) were studied over 7h following ingestion of a liquid meal containing 18g fat labelled with 250mg 13C16 palmitate, 22g protein, 36g fructose and 36g glucose. TG, 13C palmitate (13C-palm) and apoB48 concentrations were measured hourly in whole plasma and/or in chylomicrons and VLDL lipoprotein sub-fractions. OW subjects had higher chylomicron-than NW (chylo-TG 96.5 (23.1) vs 28.8 (11.8) mmol/l*420min (p=0.02)), but similar total, chylo-13C-palm and apoB48 iAUCs. In GB, chylo- 13C-palm and apoB48 increased earlier after meal ingestion, but then remained lower than in NW and OW throughout the postprandial period. GB also had lower chylo-TG iAUCs than OW (8.9 (11.5) vs 96.5 (23.2) mmol/l*420min, p=0.003). Their apoB48 iAUCs were not different from NW and OW (509.2 (90.5) vs 710.2 (80.5) and 870.1 (297.6) pg/ml*420min, all p>0.05). An accelerated postprandial apoB48 rise, together with unchanged postprandial apoB48 iUAC, suggests that intestinal fat absorption and chylomicron secretion was quantitatively unaltered, but accelerated after gastric bypass. In contrast, the decreased postprandial chylo-TG and 13C-palm iAUCs suggest that plasma chylomicron clearance was enhanced after gastric bypass.

Advanced Lipoprotein Analysis Shows Atherogenic Lipid Profile That Improves After Metreleptin in Patients with Lipodystrophy.

Patients with lipodystrophy have dyslipidemia and insulin resistance. Leptin treatment with metreleptin in lipodystrophy decreases insulin resistance and lowers triglycerides without changing high-density lipoprotein. Detailed measurement of lipoprotein particles with nuclear magnetic resonance (NMR) spectroscopy can offer insights into cardiovascular disease (CVD) risk and lipid metabolism beyond a standard lipid panel. We hypothesized that patients with lipodystrophy would have a more atherogenic lipid profile than controls at baseline, which would be ameliorated with metreleptin treatment. To characterize the lipoprotein profile in patients with lipodystrophy compared with controls and to evaluate effects of metreleptin treatment. Patients with lipodystrophy (N = 17) were studied before and after metreleptin for 2 weeks and 6 months and compared with 51 insulin-sensitive sex-matched controls. Lipoprotein profiles were measured by NMR with the LP4 deconvolution algorithm, which reports triglyceride-rich lipoprotein particles (TRLPs), high-density lipoprotein particles (HDLPs), and low-density lipoprotein particles (LDLPs). Patients with lipodystrophy had elevated large TRLPs and smaller HDLPs and LDLPs compared with controls. Five patients with lipodystrophy had chylomicrons, compared with zero controls. Metreleptin decreased the size and concentration of TRLPs, eliminated chylomicrons in all but one patient, decreased LDLPs, and increased LDLP size. Metreleptin treatment did not have major effects on HDLPs. Patients with lipodystrophy had an atherogenic lipoprotein profile at baseline consistent with elevated CVD risk, which improved after metreleptin treatment. The presence of fasting chylomicrons in a subset of patients with lipodystrophy suggests saturation of chylomicron clearance by lipoprotein lipase.

Effect of Vitamin D3 on the Postprandial Lipid Profile in Obese Patients: A Non-Targeted Lipidomics Study.

Postprandial lipemia can lead to an accumulation of atherogenic lipoproteins in the circulation associated with systemic low-grade inflammation and an increased risk of cardiovascular disease. Lifestyle and pharmacological treatments are usually prescribed for prevention. Vitamin D3 (cholecalciferol), as an anti-atherogenic agent, is being taken into consideration due to its potential beneficial effects in lipid metabolism and its anti-inflammatory potency. To assess the effects of vitamin D3 in the postprandial lipid profile in obese, vitamin D-deficient women, a non-targeted lipidomics approach using liquid chromatography coupled to a quadrupole time-of flight mass spectrometer was used to identify and quantitate a wide-range of circulating lipid species, including diglycerides, lysophosphatidylcholines, phosphatidylcholines, phosphatidylethanolamines, sphingomyelins and triglycerides. The most important changes were found in plasmatic sphingomyelin levels, which experience a decrease after vitamin D3 intake. Our results suggest a turnover of sphingomyelins, probably due to an increased activity of neutral sphingomyelinases, and, therefore, with implications in the clearance of chylomicrons, LDL and VLDL, decreasing postprandial inflammation and macrophage adherence to endothelia, potentially improving cardiovascular disease risk.

SAT-081 Advanced Lipoprotein Analysis Demonstrates Atherogenic Lipid Profile in Patients with Lipodystrophy That Improves after Metreleptin Treatment

Lipodystrophies (LD) are defined by deficient adipose tissue, causing low leptin and metabolic disease including severe insulin resistance and hypertriglyceridemia. Recombinant leptin (metreleptin, ML) treatment in LD improves insulin resistance and lowers triglycerides without changing HDL. Detailed measurement of lipoprotein particles using NMR spectroscopy can offer insights into cardiovascular disease (CVD) risk and lipid metabolism beyond a standard lipid panel and has never been performed in LD. We hypothesized that patients with LD would have a more atherogenic lipid profile than controls at baseline, which would be ameliorated with ML treatment secondary to improvements in insulin sensitivity. Patients with LD (N=17) were enrolled in a study evaluating short- and long-term effects of ML on metabolic disease and compared to 51 insulin sensitive (SI<3 on IV glucose tolerance test) sex-matched controls. Lipoprotein profiles were assessed on samples obtained after a 10-12 hour fast using a new deconvolution algorithm, LP4, which reports 27 triglyceride rich lipoprotein particles (TRLP) and 7 HDL particles (HDLP). The major categories are small, medium, and large HDLP and LDL particles (LDLP) and very small, small, medium, large, and very large TRLP. LP4 was compared in controls vs. patients with LD prior to ML. LP4 was compared in patients with LD before vs. after 14 days and 6 months of ML. Particle size, concentration, and concentration of subclasses by size were measured for LDLP, HDLP, and TRLP. Insulin sensitivity before and after ML was measured as glucose disposal (mg/kgFFM/min) during hyperinsulinemic euglycemic clamp. Patients and controls did not differ by age, weight, or BMI. Patients with LD had elevated large TRLP and smaller sized HDLP and LDLP, all associated with increased atherogenicity, vs. controls. Five of 17 patients with LD had chylomicrons present, vs. 0 of 51 controls. ML treatment in LD decreased size and concentration of TRLP, eliminated chylomicrons in all but 1 patient, decreased LDLP concentration, and increased LDLP size. ML treatment did not have major effects on HDLP. Prior to ML in patients with LD, insulin sensitivity negatively correlated with very large TRLP (r= -0.76, p= 0.0007), TRLP size (r= -0.52, p= 0.04), and TRLP TG (r= -0.58, p= 0.02). Short term (Day 0 to Day 14) and long-term changes (Day 0 to 6 months) in insulin sensitivity were not significantly correlated with changes in any lipoprotein parameter. In conclusion, patients with LD had an atherogenic lipoprotein profile at baseline consistent with increased CVD risk, which improved after ML treatment. The presence of fasting chylomicrons in a subset of patients with LD suggests saturation of chylomicron clearance by lipoprotein lipase. Improvements in lipoprotein parameters with ML were independent of improved insulin sensitivity, possibly due to direct effects of ML on lipoprotein metabolism.

Apolipoprotein E gene polymorphism and renal function are associated with apolipoprotein E concentration in patients with chronic kidney disease

BackgroundChronic kidney disease (CKD) associates with complex lipoprotein disturbances resulting in high cardiovascular risk. Apolipoprotein E (APOE) is a polymorphic protein with three common isoforms (E2; E3; E4) that plays a crucial role in lipoprotein metabolism, including hepatic clearance of chylomicrons and very low-density lipoprotein (VLDL) remnants, and reverse cholesterol transport. It demonstrates anti-atherogenic properties but data concerning the link between polymorphism and level of APOE in CKD patients are inconclusive.The aim of our research was to assess the relationship between APOE gene polymorphism and APOE concentration and its redistribution among lipoproteins along with CKD progression.Methods90 non-dialysed CKD patients were included into the study. Real time PCR was used for APOE genotyping. APOE level was measured in serum and in isolated lipoprotein fractions (VLDL; IDL + HDL; HDL). Kidney function was assessed using eGFR CKD-EPI formula.ResultsThe population was divided into three APOE genotype subgroups: E2(ε2ε3), E3(ε3ε3) and E4(ε3ε4). The highest APOE level was observed for the E2 subgroup (p < 0.001). APOE concentration positively correlated with eGFR value in the E2 subgroup (r = 0.7, p < 0.001) but inversely in the E3 subgroup (r = − 0.29, p = 0.02).). A lower concentration of APOE in the E2 subgroup was associated with its diminished contents in HDL and IDL + LDL particles. In the E3 subgroup, the higher concentration of APOE was related to the increased number of non-HDL lipoproteins.ConclusionIn patients with CKD, APOE genotype as well as renal function are associated with the concentration of APOE and its redistribution among lipoprotein classes.

The Association of Polyunsaturated Fatty Acid δ-5-Desaturase Activity with Risk Factors for Type 2 Diabetes Is Dependent on Plasma ApoB-Lipoproteins in Overweight and Obese Adults

δ-5 and δ-6 desaturases (D5D and D6D) catalyze the endogenous conversion of n-3 (ω-3) and n-6 (ω-6) polyunsaturated fatty acids (PUFAs). Their activities are negatively and positively associated with type 2 diabetes (T2D), respectively, by unclear mechanisms. Elevated plasma apoB-lipoproteins (measured as plasma apoB), which can be reduced by n-3 PUFA intake, promote T2D risk factors. The aim of this study was to test the hypothesis that the association of D5D and D6D activities with T2D risk factors is dependent on plasma apoB. This is a pooled analysis of 2 populations recruited for 2 different metabolic studies. It is a post hoc analysis of baseline data of these subjects [n=98; 60% women (postmenopausal); mean ± SD body mass index (in kg/m2): 32.8±4.7; mean ± SD age: 57.6±6.3 y]. Glucose-induced insulin secretion (GIIS) and insulin sensitivity (IS) were measured using Botnia clamps. Plasma clearance of a high-fat meal (600 kcal/m2, 66% fat) and white adipose tissue (WAT) function (storage of 3H-triolein-labeled substrate) were assessed in a subpopulation (n=47). Desaturase activities were estimated from plasma phospholipid fatty acids. Associations were examined using Pearson and partial correlations. While both desaturase activities were positively associated with percentage of eicosapentaenoic acid, only D5D was negatively associated with plasma apoB (r=-0.30, P=0.003). Association of D5D activity with second-phase GIIS (r=-0.23, P=0.029), IS (r=0.33, P=0.015, in women) and 6-h area-under-the-curve (AUC6h) of plasma chylomicrons (apoB48, r=-0.47, P=0.020, in women) was independent of age and adiposity, but was eliminated after adjustment for plasma apoB. D6D activity was associated in the opposite direction with GIIS (r=0.24, P=0.049), IS (r=-0.36, P=0.004) and AUC6h chylomicrons (r=0.52, P=0.004), independent of plasma apoB. Both desaturases were associated with plasma interleukin-1-receptor antagonist (D5D: r=-0.45, P<0.001 in women; D6D: r=-0.33, P=0.007) and WAT function (trend for D5D: r=0.30, P=0.05; D6D: r=0.39, P=0.027) independent of any adjustment. Association of D5D activity with IS, lower GIIS, and plasma chylomicron clearance is dependent on plasma apoB in overweight and obese adults.

Intestine‐Specific Overexpression of Carboxylesterase 2c Protects Mice From Diet‐Induced Liver Steatosis and Obesity

Murine hepatic carboxylesterase 2c (Ces2c) and the presumed human ortholog carboxylesterase 2 (CES2) have been implicated in the development of nonalcoholic fatty liver disease (NAFLD) in mice and obese humans. These studies demonstrated that Ces2c hydrolyzes triglycerides (TGs) in hepatocytes. Interestingly, Ces2c/CES2 is most abundantly expressed in the intestine, indicating a role of Ces2c/CES2 in intestinal TG metabolism. Here we show that Ces2c is an important enzyme in intestinal lipid metabolism in mice. Intestine‐specific Ces2c overexpression (Ces2cint) provoked increased fatty acid oxidation (FAO) in the small intestine accompanied by enhanced chylomicron clearance from the circulation. As a consequence, high‐fat diet–fed Ces2cint mice were resistant to excessive diet‐induced weight gain and adipose tissue expansion. Notably, intestinal Ces2c overexpression increased hepatic insulin sensitivity and protected mice from NAFLD development. Although lipid absorption was not affected in Ces2cint mice, fecal energy content was significantly increased. Mechanistically, we demonstrate that Ces2c is a potent neutral lipase, which efficiently hydrolyzes TGs and diglycerides (DGs) in the small intestine, thereby generating fatty acids (FAs) for FAO and monoglycerides (MGs) and DGs for potential re‐esterification. Consequently, the increased availability of MGs and DGs for re‐esterification and primordial apolipoprotein B48 particle lipidation may increase chylomicron size, ultimately mediating more efficient chylomicron clearance from the circulation. Conclusion: This study suggests a critical role for Ces2c in intestinal lipid metabolism and highlights the importance of intestinal lipolysis to protect mice from the development of hepatic insulin resistance, NAFLD, and excessive diet‐induced weight gain during metabolic stress.

Everolimus-Induced Hypertriglyceridemia Manifesting as Acute Pancreatitis

Everolimus is used in the treatment of many advanced cancers like renal and breast cancer. Hypertriglyceridemia (HTG) is a known adverse effect of the drug. However, acute pancreatitis (AP) is not commonly reported. A 46-year-old Hispanic female with recurrent breast cancer had been treated with Everolimus (10 mg/day) for 6 weeks, who then developed elevated triglycerides (TG) and the Everolimus was stopped. Three days later, she presented to the emergency center with nausea and severe, mid-epigastric pain radiating to her back. Lab values included: sodium 127 mEq/L, lipase 795 U/L, blood glucose > 700 mg/dl, with normal calcium. The serum was milky in appearance, with TG > 1590 mg/dL. There was no history of diabetes or alcohol use. She was diagnosed with diabetic ketoacidosis (DKA) and admitted to the medical ICU for intravenous fluids, insulin drip and pain control. Despite resolution of ketoacidosis, her pain worsened and she remained anorexic. Gastroenterology was consulted and diagnosed her with AP due to HTG. After several days, her TG decreased to 336 mg/dL with above treatment, coinciding with improvement of her symptoms (Figure 1). Her diet was advanced and she was discharged with fenofibrates. TG level four months later normalized. Everolimus treatment was not re-attempted. Hypertriglyceridemia and drugs are common causes of AP. There are two main causes of HTG-induced AP (HTG-AP): primary (usually genetic or idiopathic) and secondary. The pathogenesis of HTG associated with mTOR inhibitors is unclear, but may be related to slow degradation of apolipoprotein B100 leading to dyslipidemia. Hyperlipidemia is thought to cause AP when the pancreatic lipase hydrolyzes the excess TGs circulating in the serum damaging the free fatty acids which in turn accumulate in the pancreas leading to severe inflammation of the pancreas. HTG also leads to impaired clearance of chylomicrons leading to pancreatic capillary hyperviscosity causing ischemia. HTG-induced AP may be clinically evident when TG levels exceed 1000 mg/dL. Treatment involves IV insulin, IV heparin, or plasmapheresis (in absence of hyperglycemia) with fenofibrates for long term management. Our patient likely had secondary HTG due to Everolimus. Awareness of Everolimus causing HTG-AP is important for gastroenterologists, especially those who may treat cancer patients.Figure: Timeline showing introduction of Everolimus and development of Hypertriglyceridemia.

ApoB-lipoproteins and dysfunctional white adipose tissue: Relation to risk factors for type 2 diabetes in humans

Elevated plasma apoB is an independent predictor of T2D; however, underlying mechanisms remain unclear. Chronic reduction in white adipose tissue (WAT) function promotes T2D. We reported that differentiation of preadipocytes and acute incubation of human WAT with LDL induce their dysfunction (decreased hydrolysis and storage of triglyceride-rich lipoproteins [TRL]). To examine the hypothesis that the association of plasma apoB with T2D risk factors, hypertriglyceridemia (hyperTG), insulin resistance (IR), and hyperinsulinemia, was dependent on WAT dysfunction. Thirty normoglycemic subjects were enrolled (≥27kg/m2, 45-74years). Fasting gynoid WAT biopsy was obtained followed by the ingestion of a 13C-triolein-labeled-high-fat meal. WAT function was measured exvivo as the hydrolysis and storage of 3H-triolein-labeled-TRL as 3H-lipids over 4 hours. Insulin sensitivity and secretion were measured by Botnia clamps. WAT function correlated with higher insulin sensitivity (M/Iclamp r=0.60) and faster plasma clearance of chylomicrons in women (iAUC6hrs apoB48, r=-0.60). Plasma apoB correlated with WAT dysfunction (r=-0.52), postprandial hyperTG (iAUC6hrs-TG, r=0.51, 13C-TG, r=0.48), IR (M/Iclamp r=-0.38) and hyperinsulinemia (second phase-glucose-induced-insulin-secretion, r=0.41). Co-incubation of subjects' WAT with their LDL increased medium accumulation of 3H-TRL and 3H-NEFA with no sex differences. Adjusting for WAT function eliminated the association of plasma apoB with IR independent of sex and body fat or adipocyte diameter. Its association with other risk factors was unaffected. Association of plasma apoB with IR in obese subjects is dependent on gynoid WAT dysfunction. We propose that targeting hyperapoB, without increasing their uptake into nonhepatic peripheral tissues, ameliorates WAT function and risk for T2D.

ChemInform Abstract: Effects of Lipid Structure Changed by Interesterification on Melting Property and Lipemia

AbstractReview: 76 refs.

Effects of Lipid Structure Changed by Interesterification on Melting Property and Lipemia.

Interesterification or the randomization reaction changes fatty acid positional distribution and solid fat content of fats, which may consequently affect fat absorption and metabolism. It is well established that saturated fatty acids in the sn-2 position of triacylglycerols (TAG) have better digestibility and lower postprandial chylomicron clearance compared to those in the sn-1,3 positions in animal experiments. TAG structure is also shown to affect fasting lipid level and atherosclerosis in animals, but fat interesterification it has been shown to not affect fasting lipid level in human adults. However, its effect on postprandial responses is controversial. In this review, the complex results of studies of interesterification and lipemia were briefly discussed. More importantly, the confounding of two factors that are both changed by interesterification, TAG structure and solid fat content as the main limitation on understanding how interesterification affects lipemia is emphasized. Separation of the two factors is possible using paired fats as demonstrated. This paper also discusses some intriguing effects of fats having saturated fatty acids in the sn-2 position and the need for future research.