Increased Lipoprotein Lipase Activity Research Articles

Xanthohumol, a prenylated chalcone, regulates lipid metabolism by modulating the LXRα/RXR-ANGPTL3-LPL axis in hepatic cell lines and high-fat diet-fed zebrafish models

Angiopoietin-like 3 (ANGPTL3) acts as an inhibitor of lipoprotein lipase (LPL), impeding the breakdown of triglyceride-rich lipoproteins (TGRLs) in circulation. Targeting ANGPTL3 is considered a novel strategy for improving dyslipidemia and atherosclerotic cardiovascular diseases (ASCVD). Hops (Humulus lupulus L.) contain several bioactive prenylflavonoids, including xanthohumol (Xan), isoxanthohumol (Isoxan), 6-prenylnaringenin (6-PN), and 8-prenylnaringenin (8-PN), with the potential to manage lipid metabolism. The aim of this study was to investigate the lipid-lowering effects of Xan, the effective prenylated chalcone in attenuating ANGPTL3 transcriptional activity, both in vitro using hepatic cells and in vivo using zebrafish models, along with exploring the underlying mechanisms. Xan (10 and 20 μM) significantly reduced ANGPTL3 mRNA and protein expression in HepG2 and Huh7 cells, leading to a marked decrease in secreted ANGPTL3 proteins via hepatic cells. In animal studies, orally administered Xan significantly alleviated plasma triglyceride (TG) and cholesterol levels in zebrafish fed a high-fat diet. Furthermore, it reduced hepatic ANGPTL3 protein levels and increased LPL activity in zebrafish models, indicating its potential to modulate lipid profiles in circulation. Furthermore, molecular docking results predicted that Xan exhibits a higher binding affinity to interact with liver X receptor α (LXRα) and retinoic acid X receptor (RXR) than their respective agonists, T0901317 and 9-Cis-retinoic acid (9-Cis-RA). We observed that Xan suppressed hepatic ANGPTL3 expression by antagonizing the LXRα/RXR-mediated transcription. These findings suggest that Xan ameliorates dyslipidemia by modulating the LXRα/RXR-ANGPTL3-LPL axis. Xan represents a novel potential inhibitor of ANGPTL3 for the prevention or treatment of ASCVD.

23-OR: Reduction in Insulin Uncovers a Novel Effect of VEGFB on Cardiac Substrate Utilization

VEGFB is known to up-regulate FA delivery through its effect on EC FA transporters. In its absence, intracellular lipid accumulation was reduced. Paradoxically, cardiac-specific overexpression of VEGFB demonstrated a lowered heparin-releasable lipoprotein lipase (LPL) activity with reduced FA utilization in vivo. Currently, the mechanism behind this in vivo metabolic effect of VEGFB on cardiac LPL is unclear. In transgenic (Tg) hearts, the vectorial transfer of LPL from myocytes to the vascular lumen is obstructed, resulting in LPL buildup within cardiomyocytes. Given that insulin is known to inhibit LPL translocation and thus FA metabolism in the heart, this observation is likely a secondary effect of VEGFB on vascular development with its associated augmentation of insulin delivery. We tested whether lowering of insulin by fasting would validate our hypothesis. WT fasted hearts enhanced their heparin-releasable LPL activity in an attempt to switch substrate utilization to FA. Intriguingly, this increase in LPL activity following fasting was even more dramatic in Tg hearts. Thus, with insulin deficiency following fasting, VEGFB works unimpeded to facilitate LPL movement. This effect occurred through the activation of p38 MAPK. PET imaging using 18FTHA revealed augmented LPL-derived FA and impaired FDG glucose uptake in the Tg fasted heart. Additionally, this increased delivery of LPL-derived FA correlated to augmented mitochondrial oxidation determined by high resolution oxygraphy. We examined whether this property of VEGFB on FA uptake and oxidation could be useful following diabetes, with its attendant loss of metabolic flexibility. Unexpectedly, in Tg hearts, diabetes inhibited myocyte VEGFB gene expression and protein secretion together with its downstream receptor signaling. Our data suggests that following diabetes, loss of VEGFB action may contribute towards the metabolic inflexibility, lipotoxicity and diabetic cardiomyopathy. Disclosure R.Shang: None. C.Lee: None. B.Hussein: None. B.Rodrigues: None. Funding Canadian Institutes of Health Research (PJT180558); Diabetes Canada (OG3215585BR)

Angiopoietin-like protein 4/8 complex-mediated plasmin generation leads to cleavage of the complex and restoration of LPL activity

Triglyceride (TG) metabolism is highly regulated by angiopoietin-like protein (ANGPTL) family members [Y. Q. Chen et al.,J. Lipid Res. 61,1203-1220 (2020)]. During feeding, ANGPTL8 forms complexes with the fibrinogen-like domain-containing protein ANGPTL4 in adipose tissue to decrease ANGPTL3/8- and ANGPTL4-mediated lipoprotein lipase (LPL)-inhibitory activity and promote TG hydrolysis and fatty acid (FA) uptake. The ANGPTL4/8 complex, however, tightly binds LPL and partially inhibits it invitro. To try to reconcile the invivo and invitro data on ANGPTL4/8, we aimed to find novel binding partners of ANGPTL4/8. To that end, we performed pulldown experiments and found that ANGPTL4/8 bound both tissue plasminogen activator (tPA) and plasminogen, the precursor of the fibrinolytic enzyme plasmin. Remarkably, ANGPTL4/8 enhanced tPA activation of plasminogen to generate plasmin in a manner like that observed with fibrin, while minimal plasmin generation was observed with ANGPTL4 alone. The addition of tPA and plasminogen to LPL-bound ANGPTL4/8 caused rapid, complete ANGPTL4/8 cleavage and increased LPL activity. Restoration of LPL activity in the presence of ANGPTL4/8 was also achieved with plasmin but was blocked when catalytically inactive plasminogen (S760A) was added to tPA or when plasminogen activator inhibitor-1 was added to tPA+ plasminogen, indicating that conversion of plasminogen to plasmin was essential. Together, these results suggest that LPL-bound ANGPTL4/8 mimics fibrin to recruit tPA and plasminogen to generate plasmin, which then cleaves ANGPTL4/8, enabling LPL activity to be increased. Our observations thus reveal a unique link between the ANGPTL4/8 complex and plasmin generation.

Feed restriction as a tool for further studies describing the mechanisms underlying lipolysis in milk in dairy cows

Milk lipolysis is defined as the hydrolysis of triglycerides, which are the main component of milk fat. Short-chain fatty acids (FAs) released in milk are responsible for rancid flavour. In addition, the presence of partial glycerides impairs the functional properties of milk, such as foaming and creaming abilities. Milk lipolysis, a key criterion used to assess milk quality, depends on animal parameters and breeding factors. Low-energy diets are associated with higher levels of spontaneous lipolysis, particularly in late lactation. In this study, dairy cows were fed a restricted diet (i.e. 65% of their ad libitum DM intake (DMI)) to induce spontaneous lipolysis in milk and to study milk composition associated with lipolysis. Two groups of 22 cows each received a control diet (100% of ad libitum DMI) or the restricted diet according to a 2 × 2 crossover design. The restricted diet was fed for five days. As expected, feed restriction increased milk spontaneous lipolysis which was associated with an increase in lipoprotein lipase activity. At the same time, milk yield and protein content decreased and no effect was observed on milk fat content. The increase in spontaneous lipolysis was associated with an increase in milk fat globules diameter, without influencing casein micelles diameter. Feed restriction altered the parameters of dairy cow metabolism, with increases in plasma non-esterified FAs, triglycerides and urea, indicating body fat mobilisation and protein catabolism associated with feed restriction. Feed restriction also altered hormonal parameters, with decreases in plasma insulin, insulin-like growth factor 1 and prolactin. As expected, lipolysis was higher in evening milk and was associated with a larger diameter of milk fat globules. This zootechnical approach will be completed with proteomic, lipidomic and transcriptomic studies of milk and/or mammary gland of animals selected for their extreme lipolysis.

A hepatokine derived from the ER protein CREBH promotes triglyceride metabolism by stimulating lipoprotein lipase activity.

The endoplasmic reticulum (ER)-tethered, liver-enriched stress sensor CREBH is processed in response to increased energy demands or hepatic stress to release an amino-terminal fragment that functions as a transcription factor for hepatic genes encoding lipid and glucose metabolic factors. Here, we discovered that the carboxyl-terminal fragment of CREBH (CREBH-C) derived from membrane-bound, full-length CREBH was secreted as a hepatokine in response to fasting or hepatic stress. Phosphorylation of CREBH-C mediated by the kinase CaMKII was required for efficient secretion of CREBH-C through exocytosis. Lipoprotein lipase (LPL) mediates the lipolysis of circulating triglycerides for tissue uptake and is inhibited by a complex consisting of angiopoietin-like (ANGPTL) 3 and ANGPTL8. Secreted CREBH-C blocked the formation of ANGPTL3-ANGPTL8 complexes, leading to increased LPL activity in plasma and metabolic tissues in mice. CREBH-C administration promoted plasma triglyceride clearance and partitioning into peripheral tissues and mitigated hypertriglyceridemia and hepatic steatosis in mice fed a high-fat diet. Individuals with obesity had higher circulating amounts of CREBH-C than control individuals, and human CREBH loss-of-function variants were associated with dysregulated plasma triglycerides. These results identify a stress-induced, secreted protein fragment derived from CREBH that functions as a hepatokine to stimulate LPL activity and triglyceride homeostasis.

Ethyl EPA and ethyl DHA cause similar and differential changes in plasma lipid concentrations and lipid metabolism in subjects with low-grade chronic inflammation

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to similarly lower plasma TG concentrations but differentially regulate plasma LDL-C and HDL-C concentrations. The aim of this study was to evaluate the common and differential effects of these ω-3 fatty acids on plasma lipids and lipoproteins and to assess the metabolic mechanisms of the effects. In a randomized, double-blind, crossover study, we assessed the effect of 10-week supplementation with 3 g/d pure EPA and pure DHA (both as ethyl ester, ≥97% purity) on plasma lipid and lipoprotein concentrations and activities of lipoprotein lipase (LPL), cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyl transferase (LCAT) in 21 older (>50 y) men and postmenopausal women with some characteristics of metabolic syndrome and low-grade chronic inflammation. Both EPA and DHA lowered plasma TG concentrations and increased LDL-C/apoB and HDL-C/apoA-I ratios, but only DHA increased LDL-C concentrations. The reductions in plasma TG were inversely associated with the changes in LPL activity after both EPA and DHA supplementation. EPA lowered CETP, while DHA lowered LCAT activity. EPA and DHA worked differently in men and women, with DHA increasing LPL activity and LDL-C concentrations in women, but not in men. EPA and DHA exerted similar effects on plasma TG, but differences were observed in LDL-C concentrations and activities of some enzymes involved in lipoprotein metabolism. It was also noted that EPA and DHA worked differently in men and women, supporting sex-specific variations in lipoprotein metabolism.

Maternal obesity: new placental paradigms unfolded.

The prevalence of maternal obesity is increasing at an alarming rate, and is providing a major challenge for obstetric practice. Adverse effects on maternal and fetal health are mediated by complex interactions between metabolic, inflammatory, and oxidative stress signaling in the placenta. Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are common downstream pathways of cell stress, and there is evidence that this conserved homeostatic response may be a key mediator in the pathogenesis of placental dysfunction. We summarize the current literature on the placental cellular and molecular changes that occur in obese women. A special focus is cast onto placental ER stress in obese pregnancy, which may provide a novel link for future investigation.

Volanesorsen, an antisense oligonucleotide to apolipoprotein C-III, increases lipoprotein lipase activity and lowers triglycerides in partial lipodystrophy

BackgroundPartial lipodystrophy (PL) syndromes involve deficiency of adipose tissue, causing severe insulin resistance and hypertriglyceridemia. Apolipoprotein C-III (apoC-III) is elevated in PL and is thought to contribute to hypertriglyceridemia by inhibiting lipoprotein lipase (LPL). ObjectiveWe hypothesized that volanesorsen, an antisense oligonucleotide to apoC-III, would decrease apoC-III, increase LPL activity, and lower triglycerides in PL. MethodsFive adults with PL enrolled in a 16-week placebo-controlled, randomized, double blind study of volanesorsen, 300 mg weekly, followed by 1-year open label extension. ResultsWithin-subject effects of volanesorsen before and after 16 weeks of active drug are reported due to small sample size. From week 0 to 16, apoC-III decreased from median (25th, 75th %ile) 380 (246, 600) to 75 (26, 232) ng/mL, and triglycerides decreased from 503 (330, 1040) to 116 (86, 355) mg/dL while activation of LPL by subjects’ serum increased from 21 (20, 25) to 36 (29, 42) nEq/mL*min. Although, A1c did not change, peripheral and hepatic insulin sensitivity (glucose disposal and suppression of glucose production during hyperinsulinemic clamp) increased and palmitate turnover decreased. After 32-52 weeks of volanesorsen, liver fat decreased. Common adverse events included injection site reactions and decreased platelets. ConclusionsIn PL, volanesorsen decreased apoC-III and triglycerides, in part through an LPL dependent mechanism, and may improve insulin resistance and hepatic steatosis.

The Potential of ANGPTL8 Antagonism to Simultaneously Reduce Triglyceride and Increase HDL-Cholesterol Plasma Levels.

Elevated triglyceride (TG) and reduced high-density lipoprotein-cholesterol (HDL-C) plasma levels are risk factors for atherosclerosis and cardiovascular disease. Therefore, a drug that simultaneously reduces TG and increases HDL-C plasma levels has the potential to prevent and treat these diseases. Angiopoietin-like 3 (ANGPTL3) regulates plasma TG and HDL-C levels by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL), respectively. ANGPTL3 inhibition of LPL requires complex formation with ANGPTL8, which is not required for its inhibition of EL. Therefore, the entire pool of plasma ANGPTL3 can be classified as ANGPTL8-associated ANGPTL3 and ANGPTL8-free ANGPTL3, where the former inhibits LPL and the latter inhibits EL. ANGPTL8 antibodies or inhibitors that block its interactions with ANGPTL3 can disrupt or preclude the ANGPTL3-8 complex formation, resulting in fewer ANGPTL3-8 complexes (reduced LPL inhibition), but more free ANGPTL3 (enhanced EL inhibition). Therefore, ANGPTL8 antagonism increases LPL activity while decreasing EL activity, thus leading to reduced plasma TG while simultaneously increasing HDL-C levels. In humans, carriers of ANGPTL8 truncating variants consistently have lower TG but higher HDL-C levels, supporting this hypothesis.

Effects of varied molecular weight of chitosan oligosaccharides on growth performance, carcass trait, meat quality, and fat metabolism in indigenous yellow-feathered chickens

The effect of varied molecular weight ( MW ) chitosan oligosaccharides ( COS ) supplementation on growth performance, carcass trait, meat quality and fat metabolism in indigenous yellow-feathered chickens was investigated. A total of 400-day-old female Lingnanhuang yellow-feathered chicks were randomly allotted to 1 of 5 treatments (8 replicate cages of 10 chicks per cage) and fed a corn-soybean meal based diet containing 5.8 g/kg of COS with MW of 0 (control), 600 ( Cs6 ), 1,200 ( Cs12 ), 2,400 ( Cs24 ), and 3,600 ( Cs36 ) Da for 56 d. The birds in Cs36 group exhibited better overall (0–56 d) feed efficiency ( P < 0.05). Both Cs24 and Cs36 feeding decreased ( P < 0.05) the liver and abdominal fat but only Cs36 decreased ( P < 0.05) the subcutaneous fat. In the Cs24 and Cs36 groups, there was an improvement in the meat quality as evidenced by a decrease ( P < 0.05) in drip loss of breast muscle as compared with the control and Cs6 groups. The liver lipid catabolism was enhanced ( P < 0.05) by the 2,400 Da and 3,600 Da COS caused by an increase in lipoprotein lipase activity and mRNA expression, which might also be the reason for the reduced carcass fat deposition. In conclusion, the 3,600 Da COS supplementation significantly improved the overall feed conversion ratio of indigenous yellow-feathered chickens. Both 2,400 Da and 3,600 Da COS were effective in reducing liver and abdominal fat deposition, decreasing drip loss of breast muscle and promoting liver fat catabolism. The study highlighted the importance of the chitosan oligosaccharide MW when added to chicken diets.

Volanesorsen, an Antisense Oligonucleotide to Apolipoprotein-CIII, Decreases Triglycerides and Increases Lipoprotein Lipase Activity in Partial Lipodystrophy

Partial lipodystrophy syndromes (PL) involve selective deficiency of adipose tissue, with regional deficiency of fat in the lower extremities and preservation or even excess fat in the face and neck. Clinical features typical of PL include severe insulin resistance, diabetes mellitus, hypertriglyceridemia and non-alcoholic fatty liver disease. Apolipoprotein CIII (Apo-CIII) is elevated in PL, and is thought to contribute to high TG by inhibiting lipoprotein lipase (LPL). However, prior studies of this drug in patients with LPL mutations demonstrated LPL-independent mechanisms of TG-lowering. We hypothesized that Volanesorsen, an antisense oligonucleotide (ASO) to apo-CIII, would decrease apo-CIII, increase LPL activity, and lower TG in PL. We further hypothesized that Volanesorsen would improve insulin resistance and glycemia by directing free fatty acids (FFA) into adipose tissue, rather than ectopic sites (e.g. liver) associated with insulin resistance. Five adults with PL and TG ≥500 mg/dL or TG≥200 with A1c >7.0% were enrolled in a 16-week placebo-controlled, randomized, double blind study of Volanesorsen, 300 mg SC weekly, followed by a 1-year open label extension. Here, we report within-subject effects of Volanesorsen lipids, glycemia and lipolysis, before and after 16 weeks of active drug. From week 0 to week 16, apoC-III decreased from 380 (246, 600) to 75 (26, 232) ng/mL, TG decreased from 503 (330, 1040) to 116 (86, 355) mg/dL; and LPL activity measured in post-heparin plasma utilizing the subject’s serum as activator increased from 22.0±3.0 to 35.5±5.9 nEq/ml/min. Free fatty acid turnover (measured by palmitate tracer studies) decreased from 0.41 (0.35, 0.45) to 0.25 (0.23, 0.29) mg/kg/min. There was no change in A1c (8.4±1.2 to 8.3±0.9%), however there was a decrease in HOMA-IR from 26 (20, 54) to 13 (9, 43) and an increase in peripheral insulin sensitivity (glucose infusion rate during euglycemic hyperinsulinemic clamp, 120 mU/m2/min) from 3.6±2.4 to 4.4±1.5 mg/kgFFM/min and in hepatic insulin sensitivity (% suppression of hepatic glucose production during clamp) from 78±19 to 90±13%. Adverse events include injection site reactions and decreased platelets. Volanesorsen decreased apo-CIII and triglycerides, at least in part through an LPL dependent mechanism, and may improve insulin resistance.

How adiponectin fights diabetes

Signal Transduction Adiponectin, a hormone produced in adipose tissue, may provide a useful therapeutic lead for type 2 diabetes because it improves glucose homeostasis and tissue sensitivity to insulin. But how it does so is unclear. Li et al. show that in mice with insulin resistance caused by a high-fat diet, treatment with adiponectin reduced the amount of triglyceride in the liver and in skeletal muscle. It did so by increasing lipoprotein lipase activity and triglyceride uptake into epididymal white adipose tissue and increasing fatty acid oxidation in muscle. These effects decreased the amount of diacylglycerol in the plasma membrane of liver and muscle cells, thus decreasing the activity of protein kinase C family members that impair signaling by the insulin receptor. Proc. Natl. Acad. Sci. U.S.A. 117 , 32584 (2020).

Effects and Mechanisms of Chitosan and ChitosanOligosaccharide on Hepatic Lipogenesis and Lipid Peroxidation, Adipose Lipolysis, and Intestinal Lipid Absorption in Rats with High-Fat Diet-Induced Obesity.

Chitosan and its derivative, chitosan oligosaccharide (CO), possess hypolipidemic and anti-obesity effects. However, it is still unclear if the mechanisms are different or similar between chitosan and CO. This study was designed to investigate and compare the effects of CO and high-molecular-weight chitosan (HC) on liver lipogenesis and lipid peroxidation, adipose lipolysis, and intestinal lipid absorption in high-fat (HF) diet-fed rats for 12 weeks. Rats were divided into four groups: normal control diet (NC), HF diet, HF diet+5% HC, and HF diet+5% CO. Both HC and CO supplementation could reduce liver lipid biosynthesis, but HC had a better effect than CO on improving liver lipid accumulation in HF diet-fed rats. The increased levels of triglyceride decreased lipolysis rate, and increased lipoprotein lipase activity in the perirenal adipose tissue of HF diet-fed rats could be significantly reversed by both HC and CO supplementation. HC, but not CO, supplementation promoted liver antioxidant enzymes glutathione peroxidase and superoxide dismutase activities and reduced liver lipid peroxidation. In the intestines, CO, but not HC, supplementation reduced lipid absorption by reducing the expression of fabp2 and fatp4 mRNA. These results suggest that HC and CO have different mechanisms for improving lipid metabolism in HF diet-fed rats.

New Classification and Management of Abetalipoproteinemia and Related Disorders

New Classification and Management of Abetalipoproteinemia and Related Disorders

EPA and DHA Have Differential Effects on Cholesterol Ester Transfer Protein and Lipoprotein Lipase Activities Following Plasma Triglycerides Lowering

Abstract Objectives Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are effective in reducing plasma triglyceride (TG) concentrations but have divergent effects on LDL cholesterol (LDL-C) concentrations. Differential regulations of cholesterol ester transfer protein (CETP) and lipoprotein lipase (LPL) activities are possible mechanisms of their differential effects. We assessed the effects of EPA and DHA supplementation on plasma lipid profiles and two enzyme activities involved in lipoprotein metabolism. Methods Nine men and twelve postmenopausal women (N = 21, 50–75y) with chronic inflammation (CRP &amp;gt; 2 mg/L) were enrolled in a randomized, double-blind, crossover trial consisting of a 4-wk lead-in phase with high oleic acid sunflower oil (3 g/d) followed by two 10-wk EPA and DHA supplementation phases (3 g/d each) separated by a 10-wk washout phase. Plasma was collected after the lead-in (baseline) and each n-3 fatty acid supplementation phase for analysis of TG, total cholesterol and HDL-C, and CETP and post-heparin LPL activities. LDL-C was estimated using the Friedewald formula. Results Subjects were recruited to have moderately elevated TG and LDL-C concentrations (mean ± SEM: 141 ± 11 and 130 ± 6 mg/dL, respectively). Compared to baseline, EPA supplementation lowered TG concentration (−28 ± 6 mg/dL, P &amp;lt; 0.001) and CETP activity (−1.6 ± 1.1 µg/mL/h, P &amp;lt; 0.05), whereas LDL-C concentration and LPL activity were unchanged. The changes in TG concentration and CETP activity were negatively correlated with baseline TG (r = −0.77 and −0.45, respectively, both P &amp;lt; 0.05). DHA supplementation lowered TG concentration (−31 ± 8 mg/dL, P &amp;lt; 0.001), and increased LDL-C concentration (+10 ± 4 mg/dL, P &amp;lt; 0.01) and LPL activity (+6.1 ± 4.0 mU/mL, P &amp;lt; 0.03), CETP activity was unchanged. The DHA-mediated increase in LPL activity was correlated with the baseline TG concentration and change in TG concentration (r = 0.64 and ρ = −0.45, respectively, both P &amp;lt; 0.05). Conclusions In the context of the established TG-lowering effects of EPA and DHA, these n-3 fatty acids affected CETP and LPL activities differently. DHA-induced change in LDL-C concentration may be related to increased LPL activity, and the conversion of very low-density lipoprotein to LDL. Funding Sources AFRI/NIFA; USDA.

Effect of Mirabegron on the Body's Exercise Capacity: A Review.

Mirabegron is a β3-agonist drug approved by the FDA for use in 2012 and administered in overactive bladder. Activating of adrenergic receptors leads to the relaxation of the detrusor muscle. According to the latest research and reports, it also has lipolytic activity, affecting the reduction of mainly brown adipose tissue (BAT) but also of white adipose tissue (WAT). This results in a decrease in body weight and triglyceride concentration and an increase in lipoprotein lipase activity, as well as in the level of free fatty acids or adipokines in the plasma. The drug indirectly participates in the regulation of carbohydrate metabolism, influencing the increase in insulin sensitivity, supporting cellular uptake of glucose. However, due to the elevation of blood pressure and pulse, as a supplement, the drug should be taken with care to avoid cardiovascular complications. In our review, below, we present a description and discussion of available studies in terms of mirabegron action on the exercise capacity of the body in the context of its potential use as a doping agent.

Hayeobtan ameliorates high fat/high cholesterol diet‐induced hypertriglyceridemia and endothelial dysfunction

The leaves of lotus are called ‘Hayeob’ ( ), which is known to have the effect of extinguishing heat, smoothing water metabolism, clearing the blood, and releasing blood(1–2). This experimental study was designed to investigate the inhibitory effects of Hayeobtan on lipid metabolism in high fat/cholesterol diet (HFCD)‐induced hypertriglyceridemia(3–4). Sprague Dawley rats were fed the HFCD diet with/without fluvastatin (Flu, positive control) 3 mg/kg/day, and HYT 100 or 200 mg/kg/day, respectively. All groups received a regular diet or HF diet, respectively, for 13 weeks. The last three groups treatment of Flu and HYT 100, and HYT200 orally for 9 weeks. Treatment of HYT markedly attenuated plasma levels of triglycerides and augmented plasma levels of high‐density lipoprotein (HDL) in HFCD‐fed rats. HYT and Flu also led to an increase in lipoprotein lipase activity in the HFCD group. On the other hand, HYT and Flu led to an decrease in fatty acid synthase and free fatty acid activity in the HFCD group. Treatment with HYT suppressed increased expressions of PPAR‐α and AMPK in HFCD rat liver or muscle. In addition, the HYT attenuated triglyceridemia by inhibition of PPAR‐γ and FABP protein expression levels and LXR and SREBP‐1 gene expression in liver or muscle. The HYT significantly prevented the development of the metabolic disturbances such as hypertriglyceridemia and hyperlipidemia. Taken together, the administration of HYT improves hypertriglyceridemia through the alteration in suppression of triglyceride synthesis and accentuated of triglyceride decomposition. These results suggested that HYT is useful in the prevention or treatment of hypertriglyceridemia‐related disorders such as triglyceride metabolism.Support or Funding InformationThis work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2017R1A5A2015805)(2019R1I1A3A01062432).

EPA and DHA have divergent effects on serum triglycerides and lipogenesis, but similar effects on lipoprotein lipase activity: a randomized controlled trial

Comparative studies suggest that DHA may have stronger serum triglyceride-lowering effects than EPA; however, the molecular basis for this differential effect remains unexplored in humans. Differential regulation of lipogenesis and triglyceride clearance are 2 possible mechanisms of action. We compared the effects of EPA and DHA supplementation on serum triglycerides, markers of lipogenesis, and lipoprotein lipase (LPL) activity in adults participating in a double-blind, multiarm, placebo-controlled parallel-group randomized trial. Lipogenesis was assessed with the lipogenic index and compound specific isotope analysis (CSIA). Young, healthy normolipidemic men and women (n=89; 21.6±0.23 y; mean ± SEM) were randomly allocated into 1 of 3 supplement groups for 12 wk: 1) olive oil, 2) ∼3 g EPA/d, and 3) ∼3 g DHA/d. Omega-3 supplements were provided in triglyceride form. Blood was collected before and after supplementation for the analysis of fatty acids and preheparin LPL activity. Variations in the 13C:12C ratio (δ13C) of palmitate (16:0) and linoleate (18:2n-6) were measured by CSIA. DHA supplementation reduced blood triglycerides (0.85±0.04 mmol/L to 0.65±0.03 mmol/L; P<0.01), with no change seen with EPA supplementation. DHA supplementation did not change the lipogenic index or δ13C-16:0, whereas EPA supplementation increased the lipogenic index by 11% (P<0.01) and δ13C-16:0 (P=0.03) from -23.2±0.2 to -22.8±0.2 milliUrey±SEM. Reduced triglyceride concentrations after DHA supplementation are associated with increased LPL activity, whereas the null effect of EPA supplementation on blood triglycerides may stem from the concomitant increases in lipogenesis and LPL activity. Further investigation of the differential triglyceride-lowering effects of EPA and DHA is warranted in both normolipidemic and hyperlipidemic individuals. This trial was registered at clinicaltrials.gov as NCT03378232.

Apolipoprotein C-II mimetic peptide is an efficient activator of lipoprotein lipase in human plasma as studied by a calorimetric approach

Elevated plasma triglyceride (TG) levels are associated with higher risk of atherosclerotic cardiovascular disease. One way to reduce plasma TG is to increase the activity of lipoprotein lipase (LPL), the rate limiting enzyme in plasma TG metabolism. An apolipoprotein (apo) C-II mimetic peptide (18A–CII–a) has been recently developed that stimulated LPL activity in vitro and decreased plasma TG concentration in animal models for hypertriglyceridemia. Since this peptide can serve as a new therapeutic approach for treatment of hypertriglyceridemia, we investigated how 18A–CII–a peptide influences LPL activity in human plasma. We used recently described isothermal titration calorimetry based approach to assess the peptide, which enables the analysis in nearly undiluted human plasma. The 18A–CII–a peptide was 3.5-fold more efficient in stimulating LPL activity than full-length apoC-II in plasma sample from normolipidemic individual. Furthermore, 18A–CII–a also increased LPL activity in hypertriglyceridemic plasma samples. Unlike apoC-II, high concentrations of the 18A–CII–a peptide did not inhibit LPL activity. The increase in LPL activity after addition of 18A–CII–a or apoC-II to plasma was due to the increase of the amount of available substrate for LPL. Measurements with isolated lipoproteins revealed that the relative activation effects of 18A–CII–a and apoC-II on LPL activity were greater in smaller size lipoprotein fractions, such as remnant lipoproteins, low-density lipoproteins and high-density lipoproteins. In summary, this report describes a novel mechanism of action for stimulation of LPL activity by apoC-II mimetic peptides.

Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 and angiopoietin-like protein 4 are associated with the increase of lipoprotein lipase activity in epicardial adipose tissue from diabetic patients

Background and aimsEpicardial adipose tissue (EAT) is a visceral AT, surrounding myocardium and coronary arteries. Its volume is higher in Type 2 diabetic (DM2) patients, associated with cardiovascular disease risk. Lipoprotein lipase (LPL) hydrolyses triglycerides (TG) from circulating lipoproteins, supplying fatty acids to AT, contributing to its expansion. We aimed to evaluate LPL expression and activity in EAT from DM2 and no DM2 patients, and its regulators ANGPTL4, GPIHBP1 and PPARγ levels, together with VLDLR expression and EAT LPL association with VLDL characteristics. MethodsWe studied patients undergoing coronary by-pass graft (CABG) divided into CABG-DM2 (n = 21) and CABG-noDM2 (n = 29), and patients without CABG (No CABG, n = 30). During surgery, EAT and subcutaneous AT (SAT) were obtained, in which LPL activity, gene and protein expression, its regulators and VLDLR protein levels were determined. Isolated circulating VLDLs were characterized. ResultsEAT LPL activity was higher in CABG-DM2 compared to CABG-noDM2 and No CABG (p=0.002 and p<0.001) and in CABG-noDM2 compared to No CABG (p=0.02), without differences in its expression. ANGPTL4 levels were higher in EAT from No CABG compared to CABG-DM2 and CABG-noDM2 (p<0.001). GPIHBP1 levels were higher in EAT from CABG-DM2 and CABG-noDM2 compared to No CABG (p= 0.04). EAT from CABG-DM2 presented higher PPARγ levels than CABG-noDM2 and No CABG (p=0.02 and p=0.03). No differences were observed in VLDL composition between groups, although EAT LPL activity was inversely associated with VLDL-TG and TG/protein index (p<0.05). ConclusionsEAT LPL regulation would be mainly post-translational. The higher LPL activity in DM2 could be partly responsible for the increase in EAT volume.