Catabolism Of Lipoproteins Research Articles

POS-310 DYSLIPIDEMIA IN CHRONIC KIDNEY DISEASE

Chronic kidney disease (CKD) is associated with a dyslipidemia comprised of elevated triglycerides and low HDL-cholesterol. Levels of LDL-cholesterol (and thus, total cholesterol) are generally not elevated; however, proteinuria correlates with cholesterol and triglycerides. CKD leads to a down regulation of lipoprotein lipase and the LDL-receptor, and increased triglycerides in CKD are due to delayed catabolism of triglyceride rich lipoproteins, with no differences in production rate. The prevalence of dyslipidemia increased from 45.5% in CKD stage 1 to 67.8% in CKD stage 4; similarly, the use of lipid lowering agents increased from 18.1% in CKD stage 1 to 44.7% in CKD stage 4.

Liraglutide Increases the Catabolism of Apolipoprotein B100-Containing Lipoproteins in Patients With Type 2 Diabetes and Reduces Proprotein Convertase Subtilisin/Kexin Type 9 Expression.

Dyslipidemia observed in type 2 diabetes (T2D) is atherogenic. Important features of diabetic dyslipidemia are increased levels of triglyceride-rich lipoproteins and small dense LDL particles, which all have apolipoprotein B100 (apoB100) as a major apolipoprotein. This prompted us to study the effect of the GLP-1 agonist liraglutide on the metabolism of apoB100-containing lipoproteins. We performed an in vivo kinetic study with stable isotopes (L-[1-13C]leucine) in 10 patients with T2D before and after 6 months of treatment with liraglutide (1.2 mg/day). We also evaluated in mice the effect of liraglutide on the expression of genes involved in apoB100-containing lipoprotein clearance. In patients with T2D, liraglutide treatment significantly reduced plasma apoB100 (0.93 ± 0.13 vs. 1.09 ± 0.11 g/L, P = 0.011) and fasting triglycerides (1.76 ± 0.37 vs. 2.48 ± 0.69 mmol/L, P = 0.005). The kinetic study showed a significant increase in indirect catabolism of VLDL1-apoB100 (4.11 ± 1.91 vs. 2.96 ± 1.61 pools/day, P = 0.005), VLDL2-apoB100 (5.17 ± 2.53 vs. 2.84 ± 1.65 pools/day, P = 0.008), and IDL-apoB100 (5.27 ± 2.77 vs. 3.74 ± 1.85 pools/day, P = 0.017) and in catabolism of LDL-apoB100 (0.72 ± 0.22 vs. 0.56 ± 0.22 pools/day, P = 0.005). In mice, liraglutide increased lipoprotein lipase (LPL) gene expression and reduced proprotein convertase subtilisin/kexin type 9 (PCSK9), retinol-binding protein 4 (RBP4), and tumor necrosis factor-α (TNF-α) gene expression in adipose tissue and decreased PCSK9 mRNA and increased LDL receptor protein expression in liver. In vitro, liraglutide directly reduced the expression of PCSK9 in the liver. Treatment with liraglutide induces a significant acceleration of the catabolism of triglyceride-rich lipoproteins (VLDL1, VLDL2, IDL) and LDL. Liraglutide modifies the expression of genes involved in apoB100-containing lipoprotein catabolism. These positive effects on lipoprotein metabolism may reduce cardiovascular risk in T2D.

Apolipoprotein C-III and cardiovascular diseases: when genetics meet molecular pathologies.

Cardiovascular diseases (CVD) have overtaken infectious diseases and are currently the world’s top killer. A quite strong linkage between this type of ailments and elevated plasma levels of triglycerides (TG) has been always noticed. Notably, this risk factor is mired in deep confusion, since its role in atherosclerosis is uncertain. One of the explanations that aim to decipher this persistent enigma was provided by apolipoprotein C-III (apoC-III), a small protein historically recognized as an important regulator of TG metabolism. Preeminently, hundreds of studies have been carried out in order to explore the APOC3 genetic background, as well as to establish a correlation between its variants and dyslipidemia-related disorders, pointing to an earnest predictive power for future outcomes. Among several polymorphisms reported within the APOC3, the SstI site in its 3′-untranslated region (3′-UTR) was the most consistently and robustly associated with an increased CVD risk. As more genetic data supporting its importance in cardiovascular events aggregate, it was declared, correspondingly, that apoC-III exerts various atherogenic effects, either by intervening in the function and catabolism of many lipoproteins, or by inducing endothelial inflammation and smooth muscle cells (SMC) proliferation. This review was designed to shed the light on the structural and functional aspects of the APOC3 gene, the existing association between its SstI polymorphism and CVD, and the specific molecular mechanisms that underlie apoC-III pathological implications. In addition, the translation of all these gathered knowledges into preventive and therapeutic benefits will be detailed too.

The α-defensins stimulate proteoglycan-dependent catabolism of low-density lipoprotein by vascular cells: a new class of inflammatory apolipoprotein and a possible contributor to atherogenesis

AbstractInflammation may contribute to the pathogenesis of atherosclerosis. On the basis of previous reports that human atherosclerotic lesions contain α-defensins, a class of cationic proteins released by activated neutrophils, the study was designed to ask whether defensins modulate the binding and catabolism of low-density lipoprotein (LDL) by human vascular cells. The results of the study demonstrated that defensin stimulated the binding of 125I-LDL to cultured human umbilical vein endothelial cells, smooth muscle cells, and fibroblasts approximately 5-fold in a dose-dependent and saturable manner. Defensin and LDL formed stable complexes in solution and on cell surfaces. Stimulation of LDL binding by defensin was not inhibited by antibodies against the LDL-receptor (LDL-R), or by recombinant receptor-associated protein, which blocks binding of ligands to the α2-macroglobulin receptor/LDL-R–related protein and other LDL-R family members. Furthermore, defensin stimulated the binding, endocytosis, and degradation of LDL by fibroblasts lacking LDL-R. Stimulation of LDL degradation by defensin was inhibited approximately 75% by low concentrations of heparin (0.2 units/mL) and was similarly reduced in CHO cells lacking heparan-sulfate–containing proteoglycans. The effect of defensin was substantially increased in cells overexpressing the core protein of the syndecan-1 heparan sulfate proteoglycan. The α-defensins released from activated neutrophils may provide a link between inflammation and atherosclerosis by changing the pattern of LDL catabolism from LDL-R to the less efficient LDL-R–independent, proteoglycan-dependent pathway.

New Classification and Management of Abetalipoproteinemia and Related Disorders

New Classification and Management of Abetalipoproteinemia and Related Disorders

Apolipoprotein CIII Deficiency Protects Against Atherosclerosis in Knockout Rabbits.

Apo (apolipoprotein) CIII mediates the metabolism of triglyceride (TG)-rich lipoproteins. High levels of plasma apoCIII are positively correlated with the plasma TG levels and increase the cardiovascular risk. However, whether apoCIII is directly involved in the development of atherosclerosis has not been fully elucidated. Approach and Results: To examine the possible roles of apoCIII in lipoprotein metabolism and atherosclerosis, we generated apoCIII KO (knockout) rabbits using ZFN (zinc finger nuclease) technique. On a normal standard diet, apoCIII KO rabbits exhibited significantly lower plasma levels of TG than those of WT (wild type) rabbits while total cholesterol and HDL (high-density lipoprotein) cholesterol levels were unchanged. Analysis of lipoproteins isolated by sequential ultracentrifugation revealed that reduced plasma TG levels in KO rabbits were accompanied by prominent reduction of VLDLs (very-low-density lipoproteins) and IDLs (intermediate-density lipoproteins). In addition, KO rabbits showed faster TG clearance rate after intravenous fat load than WT rabbits. On a cholesterol-rich diet, KO rabbits exhibited constantly and significantly lower levels of plasma total cholesterol and TG than WT rabbits, which was caused by a remarkable reduction of β-VLDLs-the major atherogenic lipoproteins. β-VLDLs of KO rabbits showed higher uptake by cultured hepatocytes and were cleared faster from the circulation than β-VLDLs isolated from WT rabbits. Both aortic and coronary atherosclerosis was significantly reduced in KO rabbits compared with WT rabbits. These results indicate that apoCIII deficiency facilitates TG-rich lipoprotein catabolism, and therapeutic inhibition of apoCIII expression may become a novel means not only for the treatment of hyperlipidemia but also for atherosclerosis.

PCSK9 Inhibition with alirocumab increases the catabolism of lipoprotein(a) particles in statin-treated patients with elevated lipoprotein(a)

BackgroundLipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL) particle containing apolipoprotein(a) (apo(a)) covalently linked to apolipoprotein B-100 (apoB). Statin-treated patients with elevated Lp(a) have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Recent trials show that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition decreases Lp(a) and cardiovascular events, particularly in high risk patients with elevated Lp(a). We investigated the kinetic mechanism whereby alirocumab, a PCSK9 inhibitor, lowers Lp(a) in statin-treated patients with high Lp(a) and ASCVD. MethodsThe effects of 12-week alirocumab treatment (150 mg every 2 weeks) on apo(a) kinetics were studied in 21 patients with elevated Lp(a) concentration (>0.5 g/L). Apo(a) fractional catabolic rate (FCR) and production rate (PR) were determined using intravenous D3-leucine administration, mass spectrometry and compartmental modelling. All patients were on long-term statin treatment. ResultsAlirocumab significantly decreased plasma concentrations of total cholesterol (-39%), LDL-cholesterol (-67%), apoB (-56%), apo(a) (-25%) and Lp(a) (-22%) (P< 0.001 for all). Alirocumab also significantly lowered plasma apo(a) pool size (-26%, P <0.001) and increased the FCR of apo(a) (+28%, P< 0.001), but did not alter apo(a) PR, which remained significantly higher relative to a reference group of patients on statins with normal Lp(a) (P< 0.001). ConclusionsIn statin-treated patients, alirocumab lowers elevated plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles. This may be consequent on marked upregulation of hepatic receptors (principally for LDL) and/or reduced competition between Lp(a) and LDL particles for these receptors; the mechanism could contribute to the benefit of PCSK9 inhibition with alirocumab on cardiovascular outcomes.

Therapeutic plasma exchange for the management of severe gestational hypertriglyceridaemic pancreatitis due to lipoprotein lipase mutation.

SummaryA 19-year-old female presented at 25-weeks gestation with pancreatitis. She was found to have significant hypertriglyceridaemia in context of an unconfirmed history of familial hypertriglyceridaemia. This was initially managed with fasting and insulin infusion and she was commenced on conventional interventions to lower triglycerides, including a fat-restricted diet, heparin, marine oil and gemfibrozil. Despite these measures, the triglyceride levels continued to increase as she progressed through the pregnancy, and it was postulated that she had an underlying lipoprotein lipase defect. Therefore, a multidisciplinary decision was made to commence therapeutic plasma exchange to prevent further episodes of pancreatitis. She underwent a total of 13 sessions of plasma exchange, and labour was induced at 37-weeks gestation in which a healthy female infant was delivered. There was a rapid and significant reduction in triglycerides in the 48 h post-delivery. Subsequent genetic testing of hypertriglyceridaemia genes revealed a missense mutation of the LPL gene. Fenofibrate and rosuvastatin was commenced to manage her hypertriglyceridaemia postpartum and the importance of preconception counselling for future pregnancies was discussed. Hormonal changes in pregnancy lead to an overall increase in plasma lipids to ensure adequate nutrient delivery to the fetus. These physiological changes become problematic, where a genetic abnormality in lipid metabolism exists and severe complications such as pancreatitis can arise. Available therapies for gestational hypertriglyceridaemia rely on augmentation of LPL activity. Where there is an underlying LPL defect, these therapies are ineffective and removal of triglyceride-rich lipoproteins via plasma exchange should be considered.Learning points:Hormonal changes in pregnancy, mediated by progesterone,oestrogen and human placental lactogen, lead to a two- to three-fold increase in serum triglyceride levels.Pharmacological intervention for management of gestational hypertriglyceridaemia rely on the augmentation of lipoprotein lipase (LPL) activity to enhance catabolism of triglyceride-rich lipoproteins.Genetic mutations affecting the LPL gene can lead to severe hypertriglyceridaemia.Therapeutic plasma exchange (TPE) is an effective intervention for the management of severe gestational hypertriglyceridaemia and should be considered in cases where there is an underlying LPL defect.Preconception counselling and discussion regarding contraception is of paramount importance in women with familial hypertriglyceridaemia.

Dyslipidemia as a pathogenetic factor of the progression of the chronic kidney disease

The article presents current information on the pathogenetic role of lipid metabolism disorders and the value of lipotoxicity in renal pathology, contributing to the progression of nephropathy. The detected increase in cholesterol level, TAG, LDL, decrease in plasma HDL concentration in chronic kidney disease (CKD) is accompanied by significant changes in the composition of various lipoproteins caused by changes in the expression and activity of key proteins and enzymes involved in the biosynthesis, transport, remodeling and catabolism of lipids and lipoproteins. It has been proven that dyslipidemia in CKD affects the morphological and functional state of the kidneys, contributing to the development of renal lipotoxicity processes, affecting the structural and functional state of the kidneys, initiating oxidative stress, systemic inflammation, vascular damage, and dysregulation. To date, research on the significance of dyslipidemia as a pathogenetic factor in the formation of chronic kidney disease remains insufficiently studied. Dysregulation of lipid metabolism, leading to dyslipidemia, is often an undervalued complication of CKD.

Comparative analysis of differentially expressed genes related to triglyceride metabolism between intramuscular fat and abdominal fat in broilers

ABSTRACT1. Lipid metabolism is an indispensable process in an organism, though little is known about the regulatory mechanisms of fat deposition in different types of adipose tissues.2. The differentially expressed genes related to triglyceride (TG) metabolism between abdominal and intramuscular fat (IMF) of Beijing-You chickens were investigated in this study.3. TG content in abdominal fat (AF) (349.7 mg/g) was significantly higher (P < 0.01) than in the breast and thigh (12.3 mg/g and 24.8 mg/g, respectively).4. Using Agilent chicken gene-expression profiling in adipose tissues between AF and muscle (breast and thigh), certain representative genes related to fatty acid metabolism, lipoprotein catabolism and esterification reactions were significantly upregulated (P < 0.05 or P < 0.01).5. Genes involved in fatty acid oxidation or carbohydrate utilisation were significantly up- or downregulated (P < 0.05 or P < 0.01), including those involved with highly enriched pathways of lipid metabolism (PPAR, Wnt pathway and inositol phosphate metabolism), cell junctions (focal adhesion and regulation of actin cytoskeleton) and muscle contraction.6. Overall, higher TG levels were observed in AF tissue than in adipose tissues of breast and thigh, which could be regulated through gene expression of pathways related to lipid metabolism (PPAR, Wnt pathway and inositol phosphate metabolism), cell junctions (focal adhesion and regulation of actin cytoskeleton) and muscle contraction. These results provide clues to understanding the molecular mechanisms of TG metabolism between abdominal and IMF.

Serum PCSK9 levels are increased in obese subjects and negatively correlated with a mediterranean diet score

Aim: Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with low-density lipoprotein (LDL) catabolism and is implicated in cardiovascular disease (CVD). A Mediterranean diet is a dietary pattern associated with a reduction of diabetes and CVD incidence. Aim of the study was to assess possible differences in serum PCSK9 levels between otherwise healthy drug-naïve obese subjects (n=30, age 42 ± 10y) and healthy individuals with normal body weight (n=25, age 36 ± 6y), as well as possible correlation between PCSK9 levels and a Mediterranean diet score.

Apolipoprotein C-III in triglyceride-rich lipoprotein metabolism.

Apolipoprotein (apo) C-III is a key player in triglyceride-rich lipoprotein metabolism and strongly associated with elevated plasma triglyceride levels. Several new studies added important insights on apoC-III and its physiological function confirming its promise as a valid therapeutic target. APOC3 is expressed in liver and intestine and regulates triglyceride-rich lipoprotein (TRL) catabolism and anabolism. The transcriptional regulation in both organs requires different regulatory elements. Clinical and preclinical studies established that apoC-III raises plasma triglyceride levels predominantly by inhibiting hepatic TRL clearance. Mechanistic insights into missense variants indicate accelerated renal clearance of apoC-III variants resulting in enhanced TRL catabolism. In contrast, an APOC3 gain-of-function variant enhances de novo lipogenesis and hepatic TRL production. Multiple studies confirmed the correlation between increased apoC-III levels and cardiovascular disease. This has opened up new therapeutic avenues allowing targeting of specific apoC-III properties in triglyceride metabolism. Novel in vivo models and APOC3 missense variants revealed unique mechanisms by which apoC-III inhibits TRL catabolism. Clinical trials with Volanesorsen, an APOC3 antisense oligonucleotide, report very promising lipid-lowering outcomes. However, future studies will need to address if acute apoC-III lowering will have the same clinical benefits as a life-long reduction.

Brown adipose tissue derived ANGPTL4 controls glucose and lipid metabolism and regulates thermogenesis

ObjectivesBrown adipose tissue (BAT) controls triglyceride-rich lipoprotein (TRL) catabolism. This process is mediated by the lipoprotein lipase (LPL), an enzyme that catalyzed the hydrolysis of triglyceride (TAG) in glycerol and fatty acids (FA), which are burned to generate heat. LPL activity is regulated by angiopoietin-like 4 (ANGPTL4), a secretory protein produced in adipose tissues (AT), liver, kidney, and muscle. While the role of ANGPTL4 in regulating lipoprotein metabolism is well established, the specific contribution of BAT derived ANGPTL4 in controlling lipid and glucose homeostasis is not well understood. Methods and resultsWe generated a novel mouse model lacking ANGPTL4 specifically in brown adipose tissue (BAT-KO). Here, we report that specific deletion of ANGPTL4 in BAT results in enhanced LPL activity, circulating TAG clearance and thermogenesis. Absence of ANGPTL4 in BAT increased FA oxidation and reduced FA synthesis. Importantly, we observed that absence of ANGPTL4 in BAT leads to a remarkable improvement in glucose tolerance in short-term HFD feeding. ConclusionOur findings demonstrate an important role of BAT derived ANGPTL4 in regulating lipoprotein metabolism, whole-body lipid and glucose metabolism, and thermogenesis during acute cold exposure.

THE RATIO OF LOW-DENSITY LIPOPROTEIN CHOLESTEROL TO APOLIPOPROTEIN-B AS A MARKER OF LOW-DENSITY LIPOPROTEIN PARTICLE SIZE

The aim of this study was to determine the informative value and clinical significance of the ratio of low-density lipoprotein cholesterol to apolipoprotein-B (LDL-C/apoB) in the overall evaluation of blood lipid profile atherogenicity. Material and methods. A total of 157 apparently healthy men with normolipidemia were included in the study. The plasma levels of total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), apoA-I, apoB and apoE were measured on the Powerwave 200 automated spectrophotometer (USA) with commercially available kits (Chronolab Systems, Spain). Several clinical ratios and indices of lipid metabolism were calculated. Results. The use of apoB content in low-density lipoproteins (LDL) instead of total apoB level in plasma is preferable in calculating the LDL-C/apoB ratio. Low values of the LDL-C/LDL-apoB ratio, indicating a predominance of small dense LDL particles in plasma, were associated with higher triglycerides levels and lower apoE levels. This finding indicates that apoE, being a metabolically active apolipoprotein and regulating residence of triglycerides-rich lipoproteins in plasma, can affect size of the LDL particles. Conclusion. Thus, presence of small, dense LDL particles in plasma of men with normolipidemia can be a consequence of disturbances in catabolism and metabolic turnover of lipoproteins.

Apolipoprotein(a) isoform size may influence the production and catabolism of lipoprotein(a) particles in men

Aim: Lp(a), a LDL particle covalently bound to apo(a), is associated with an increased risk of premature coronary heart disease. Apo(a) is polymorphic and plasma Lp(a) concentrations are inversely related to the apo(a) size; yet the effect of apo(a) isoform size on Lp(a) metabolism is unclear.

Xinxuekang Regulates Reverse Cholesterol Transport by Improving High-density Lipoprotein Synthesis, Maturation, and Catabolism.

Di'ao Xinxuekang (XXK) is an herbal product in China and the Netherlands that has been clinically shown to attenuate atherosclerosis; however, the underlying antiatherosclerotic mechanism remains unclear. Because of its role in cholesterol homeostasis, reverse cholesterol transport (RCT) is a potential target for these beneficial effects. This study investigated the effects of XXK on RCT and related proteins. After treating ApoE-deficient mice with XXK for 8 weeks, we observed an increase in the expression level of ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1, which in turn stimulated cholesterol efflux and reduced aortic atherosclerotic lesion area. XXK also increased high-density lipoprotein (HDL) synthesis by modulating the peroxisome proliferator-activated receptor γ/liver X receptor α/ATP-binding cassette transporter A1 pathway and promoted HDL maturity by increasing serum lecithin-cholesterol acyltransferase. In addition, XXK improved the selective uptake of HDL-cholesteryl ester by increasing the expression of scavenger receptor class B type I. This is the first study to show that XXK confers a regulation of RCT, at least in part, by improving HDL synthesis, maturation, and catabolism.

Short-term cooling increases serum triglycerides and small high-density lipoprotein levels in humans

Cold exposure and β3-adrenergic receptor agonism, which both activate brown adipose tissue, markedly influence lipoprotein metabolism by enhancing lipoprotein lipase-mediated catabolism of triglyceride-rich lipoproteins and increasing plasma high-density lipoprotein (HDL) levels and functionality in mice. However, the effect of short-term cooling on human lipid and lipoprotein metabolism remained largely elusive. The objective was to assess the effect of short-term cooling on the serum lipoprotein profile and HDL functionality in men. Body mass index-matched young, lean men were exposed to a personalized cooling protocol for 2hours. Before and after cooling, serum samples were collected for analysis of lipids and lipoprotein composition by 1H-nuclear magnetic resonance. Adenosine triphosphate-binding cassette A1 (ABCA1)-mediated cholesterol efflux capacity of HDL was measured using [3H]cholesterol-loaded ABCA1-transfected Chinese hamster ovary cells. Short-term cooling increased serum levels of free fatty acids, triglycerides, and cholesterol. Cooling increased the concentration of large very low-density lipoprotein (VLDL) particles accompanied by increased mean size of VLDL particles. In addition, cooling enhanced the concentration of small LDL and small HDL particles as well as the cholesterol levels within these particles. The increase in small HDL was accompanied by increased ABCA1-dependent cholesterol efflux invitro. Our data show that short-term cooling increases the concentration of large VLDL particles and increases the generation of small LDL and HDL particles. We interpret that cooling increases VLDL production and turnover, which results in formation of surface remnants that form small HDL particles that attract cellular cholesterol.

Macrophage catabolism of aggregated lipoproteins using a novel extracellular compartment regulates lipid accumulation during atherosclerosis

Despite impressive advances in research, prevention, and treatment, atherosclerotic vascular disease remains the leading cause of death in the developed world. Mechanisms of cholesterol accumulation in the arteries have been studied intensively, but the in vivo contributions of different pathways leading to lipid accumulation and foam cell formation are not understood. In the arteries, low‐density lipoprotein (LDL) is aggregated and bound to the extracellular matrix. When such aggregated LDL is presented to macrophages, they form a novel acidic, hydrolytic compartment that is topologically extracellular, to which lysosomal enzymes are secreted. Using state‐of‐the‐art quantitative and high resolution microscopy techniques, characterization of compartment morphology reveals how macrophages use local actin polymerization to drive plasma membrane remodeling at the interface with aggregated LDL. This leads to sequestration of aggregated LDL into topologically convoluted structures that allow acidification, catabolism and internalization of LDL. Such compartments are observed in vivo in murine atherosclerotic plaque macrophages interacting with cholesterol rich deposits. We find that a TLR4/MyD88/Syk/PI3 kinase/Akt dependent signaling pathway in macrophages regulates the formation of such catabolic compartments. Consistent with this, deficiency of TLR4 in vivo can protect macrophages from lipid accumulation in murine atherosclerotic plaques. Herein, we provide compelling evidence for a novel form of catabolism that macrophages use to degrade aggregated LDL in vivo during atherosclerosis and this process leads to foam cell formation, cell death and promotes disease progression.Support or Funding InformationThe project described was supported by National Institutes of Health grants R37‐DK27083 and R01‐HL092234. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. R.K.S is an American Heart Association Stanley Stahl Postdoctoral Fellow (ID: 15POST22990022). V.C.B.L is supported by a fellowship from CNPq “Ciência sem Fronteiras” Brazilian program. H.F.C is a Merck Life Sciences Research Foundation Fellow. The authors declare no competing financial interests.

Effects of increased body weight and short-term weight loss on serum PCSK9 levels - a prospective pilot study.

IntroductionProprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with low-density lipoprotein (LDL) catabolism, but its serum concentration is not uniformly associated with cardiovascular disease in clinical studies. Obesity is linked with increased cardiovascular risk, but the effect of increased body weight and short-term weight loss on serum PCSK9 levels is not well studied.Material and methodsThe aim of this prospective pilot study was to assess differences in serum PCSK9 levels (determined with a quantitative sandwich enzyme immunoassay) between otherwise healthy drug-naïve obese subjects and healthy individuals with normal body weight. Additionally, PCSK9 levels were determined at baseline and after a 3-month weight-loss program with a low-fat diet in a randomly assigned subgroup of the obese subjects (n = 15).ResultsObese subjects (n = 35) were older (age: 43 ±11 years) and had significantly higher body mass index, total cholesterol, triglycerides, LDL cholesterol (LDL-C), apolipoprotein B and homeostasis model assessment of insulin resistance (HOMA) index levels, as well as significantly lower high-density lipoprotein cholesterol (HDL-C) concentration, compared with normal-weight subjects (n = 20, age: 35 ±6 years). Serum PCSK9 levels were significantly higher in obese subjects compared with normal-weight individuals, even after adjustment for age, LDL-C, triglycerides, HDL-C, apolipoprotein A1, apolipoprotein B, apolipoprotein E, glucose, insulin and HOMA index levels (p = 0.018). Obese subjects experienced significant weight loss (from 109 ±22 to 104 ±23 kg, p < 0.01), but serum PCSK9 levels did not significantly change after the 3-month weight-loss program.ConclusionsSerum PCSK9 levels are higher in obese subjects than in normal-weight individuals. Short-term weight loss with a low-fat diet does not significantly affect PCSK9 levels.

FGF21 lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown adipose tissues

FGF21 decreases plasma triglycerides (TGs) in rodents and humans; however, the underlying mechanism or mechanisms are unclear. In the present study, we examined the role of FGF21 in production and disposal of TG-rich lipoproteins (TRLs) in mice. Treatment with pharmacological doses of FGF21 acutely reduced plasma non-esterified fatty acids (NEFAs), liver TG content, and VLDL-TG secretion. In addition, metabolic turnover studies revealed that FGF21 facilitated the catabolism of TRL in white adipose tissue (WAT) and brown adipose tissue (BAT). FGF21-dependent TRL processing was strongly attenuated in CD36-deficient mice and transgenic mice lacking lipoprotein lipase in adipose tissues. Insulin resistance in diet-induced obese and ob/ob mice shifted FGF21 responses from WAT toward energy-combusting BAT. In conclusion, FGF21 lowers plasma TGs through a dual mechanism: first, by reducing NEFA plasma levels and consequently hepatic VLDL lipidation and, second, by increasing CD36 and LPL-dependent TRL disposal in WAT and BAT.