Tissue Lipoprotein Lipase Activity Research Articles

Differential depot-specific effects of long-term fructose intake on lipoprotein lipase activity and adipose tissue development in lean and obese+NIDDM SHR/Ntul//-cp rats

To determine the effects of a lower glycemic index, fructose-rich diet on parameters of weight gain and adipose tissue cellularity in principle fat depots, groups of congenic lean and obese+NIDDM SHR/tul//-cp rats were fed nutritionally complete isoenergetic diets where 54% of the calories were present as cooked cornstarch (CCS diet) or equal parts CCS and fructose (the CCSF diet) plus essential fats, proteins, minerals and dietary fibers from one until 9 months of age. Initial body weights were similar in all groups. Net weight gain and final body weights of obese >>>lean and demonstrated only a modest trend toward a greater weight gain in obese animals fed the CCSF diet. Differential effects on adipocyte size and number including marked hyperplasia and hypertrophy were observed in retroperitoneal and dorsal fat pads, while the mass and cellularity of the epididymal depots were similar in all dietary and phenotype groups. Tissue Lipoprotein Lipase activity (LPLA) was similar in EPI, RP, and Dorsal fat depots in both phenotypes, but LPLA in IBAT of lean >>> obese and demonstrated a modest diet effect (CSS > CSSF) in both phenotypes. These results indicate that the long-term consumption of the high fructose diet was neither substantially beneficial nor ameliorative in contributing to the modest excess weight gain and adiposity in WAT depots of the obese phenotype of this strain, despite the lower glycemic index and slower luminal digestibility of fructose vs cornstarch when fed in isoenergetic proportions in the diet. In contrast, IBAT mass and cellularity of obese >>> lean, while IBAT LPLA of lean >>> obese, suggestive of improved insulin sensitivity. These results suggest that the excess weight gain and adiposity often attributed to the consumption of excess dietary fructose sources may be at least in part a reflection of net caloric intake and insulinogenic responses rather than the type of carbohydrate consumed. In addition, the greater IBAT mass, cellularity, and percent lipid content of the obese are consistent with early onset hyperphagia and an impaired capacity for energy expenditure via non-shivering thermogenesis and thus represent a likely contributor to the epigenetic expression and development of obesity in the obese phenotype of this strain.

Decoding the role of angiopoietin-like protein 4/8 complex–mediated plasmin generation in the regulation of LPL activity

After feeding, adipose tissue lipoprotein lipase (LPL) activity should be maximized, therefore the potent LPL-inhibitory activity of angiopoietin-like protein 4 (ANGPTL4) must be blocked by ANGPTL8 through formation of ANGPTL4/8 complexes. ANGPTL4/8 tightly binds and protects LPL but also partially inhibits its activity. Recently, we demonstrated ANGPTL4/8 also binds tissue plasminogen activator (tPA) and plasminogen to generate plasmin that cleaves ANGPTL4/8 to restore LPL activity. Although fully active LPL in the fat postprandially is desirable, ANGPTL4/8 removal could subject LPL to profound inhibition by ANGPTL3/8 (the most potent circulating LPL inhibitor), inhibition by other LPL inhibitors like ANGPTL4, ANGPTL3, and ApoC3 or interfere with ApoC2-mediated LPL activation. To understand better these potential paradoxes, we examined LPL inhibition by ANGPTL3/8, ANGPTL4, ANGPTL3, and ApoC3 and LPL stimulation by ApoC2 in the presence of ANGPTL4/8 + tPA + plasminogen. Remarkably, ANGPTL3/8-mediated LPL inhibition was almost completely blocked, with the mechanism being cleavage of fibrinogen-like domain–containing ANGPTL3 present in the ANGPTL3/8 complex. The LPL-inhibitory effects of ANGPTL4, ANGPTL3, and ApoC3 were also largely reduced in the presence of ANGPTL4/8 + tPA + plasminogen. In contrast, the ability of ApoC2 to stimulate LPL activity was unaffected by ANGPTL4/8-mediated plasmin generation. Together, these results explain how plasmin generated by increased postprandial ANGPTL4/8 levels in adipose tissue enables maximal LPL activity by preventing ANGPTL3/8, ANGPTL4, ANGPTL3, and ApoC3 from inhibiting LPL, while permitting ApoC2-mediated LPL activation to occur.

Abstract 161: Ablation Of Intracellular Lipolytic Inhibitor G0S2 Promotes Vascular Lipolysis And Alleviates Diet-induced Atherosclerosis

Adipose tissue plays a central role in the regulation of plasma triglyceride (TG) and fatty acid (FA) levels, whose elevation is associated with atherosclerotic cardiovascular disease (ASCVD). Circulating TGs are hydrolyzed by lipoprotein lipase (LPL), releasing FAs that are taken up by adipocytes. Conversely, lipolytic action of adipose tissue triglyceride lipase (ATGL) mobilizes intracellular TG storage, supplying FAs via circulation for utilization by other tissues. However, how intracellular lipolysis influences intravascular lipolysis and atherosclerotic development remains largely unknown. Herein, the current study aimed to explore the role of G0S2, a selective protein inhibitor of ATGL, in this particular context. When treated with a Western diet and antisense oligonucleotides (ASOs) targeting LDLR, mice with a global ablation of G0S2 exhibited a significantly reduced lesion formation in aorta and brachiocephalic artery than their wild type (WT) littermates. Despite of little to no impact on hypercholesterolemia, total plasma and lipoprotein-specific TG content were normalized in G0S2 -/- mice. While it did not elicit any effects on intestinal lipid adsorption and hepatic TG secretion, the G0S2 ablation resulted in considerable elevation of LPL activity and protein levels in both plasma and adipose tissue. Accordingly, these G0S2 -/- mice showed a greatly improved TG clearance upon an oral lipid challenge. Interestingly, transplantation of G0S2 -/- adipose tissue increased circulating LPL in the WD-treated WT mice, which subsequently displayed a profound reduction of plasma TG levels as well as alleviation of hepatic steatosis. By studying adipose tissue explants and primary adipocytes, we observed that the G0S2 ablation led to markedly improved insulin sensitivity, resulting in increased FOXO1 phosphorylation and decreased expression of the LPL inhibitor ANGPTL4. Together, our data indicate that in the absence of G0S2, upregulation of adipose tissue LPL plays an important role in the clearance of circulating TGs and alleviation of diet-induced hypertriglyceridemia and atherosclerosis. We thus conclude that adipocyte G0S2 acts as a critical switch of both intracellular and vascular lipolysis.

Gestational Undernutrition and the Development of Obesity in Rats

The effects of early gestational undernutrition and subsequent re-feeding patterns on offspring food intake, body weight and adiposity were examined. Pregnant rats were food restricted to 50% of their preconception intake levels during the first 2 weeks of pregnancy and were then either returned to ad libitum feeding or pair-fed to nonrestricted control rats. Male and female offspring of previously deprived, ad libitum refed mothers gained significantly more weight when fed a standard low fat, high carbohydrate diet than did control offspring. When the maintenance diet was changed at 140 days of age to a high fat diet, both groups of previously deprived male offspring gained weight at greater than control rates. In contrast, the three groups of female rats gained weight at comparable rates after the diet change. Adipocyte hypertrophy and elevated carcass lipid content were seen in high fat—fed male but not female offspring of previously deprived mothers. Adipose tissue lipoprotein lipase activity was unaffected by these manipulations.

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.

ODP192 Empagliflozin associated Euglycemic Diabetic Ketoacidosis and the Terrible Triad

Abstract Background Among diabetic patients, newer drug classes such as SGLT2i have been reported to present with Euglycemic Diabetic Ketoacidosis (eDKA), wherein these patients are without signs of elevated glucose levels. However, this condition can coexist with acute pancreatitis (AP) and hypertriglyceridemia (HTG), which is also known as the terrible triad. Clinical Case We were presented with a 31-year old diabetic male maintained on empagliflozin 25mg OD and metformin 500mg OD, discontinued his medication four months ago, and recently started retaking empagliflozin one week ago. He presented with drowsiness, severe abdominal pain rated as 9/10, and vomiting. An NGT was inserted and on further workup, acidosis was present on ABG with an anion gap of 28 mEq/L. AP was noted on abdominal ultrasound with an amylase of 768 U/L. CBG was 167mg/dL, Hba1c of 7.4%, Creatinine of 1. 05mg/dL, with ketonuria on urinalysis. Hydration was started with referral to endocrinology service. Insulin drip was started, and CBGs ranged from 145-229mg/dL while on drip. Hydration was increased accordingly, considering the patient's intake and output. Further workup was done, and lipid profile revealed severe hypertriglyceridemia at 1724.78mg/dL and elevated VLDL at 342mg/dL. Statin was prescribed, and eventually, insulin drip was titrated down with resolution of acidosis. Insulin was then shifted to subcutaneous regimen. Diet was also transitioned to clear liquids and eventually into diabetic diet. The patient was sent home and was uneventful after. eDKA develops due to increased glucagon secretion and decreased insulin production, promoting glucose to fat metabolism and ultimately stimulating ketogenesis. These agents decrease the blood glucose level by increasing urinary glucose excretion leading to a reduction in insulin secretion from the pancreatic β-cells. The terrible or enigmatic triad consisting of AP, HTG, and DKA/eDKA has been well reported but has a complex process. HTG results as a product of the reduced lipoprotein lipase activity in peripheral tissues, which decreases the removal of VLDL from the plasma. In AP cases, HTG only accounts for a minority (2-7%) of cases, but the risk was increased with levels above 1000mg/dL, such as in our patient. In the study by Simons-Linares et al., having the said triad had higher odds of having SIRS, shock, sepsis, and parenteral nutrition when compared to AP patients alone. eDKA patients can present with non-specific signs and symptoms such as nausea, vomiting, and abdominal pain, which can delay the diagnosis in patients. Fortunately, it was recognized early on, and there was a quick response in managing the case. Conclusion To date, there is scarcity among reports of the terrible triad, especially with empagliflozin use. Therefore, we can stress the importance of keen assessments and history taking in detecting the triad for an early aggressive approach to prevent adverse outcomes. Presentation: No date and time listed

Epicardial Adipose Tissue Ceramides Are Related to Lipoprotein Lipase Activity in Coronary Artery Disease: Unfolding a Missing Link.

Epicardial adipose tissue (EAT) contributes to coronary artery disease (CAD). EAT presents a specific lipidomic signature, showing increased ceramides and other proinflammatory lipids content. Besides, LPL (lipoprotein lipase) activity in EAT would contribute to its expansion, supplying fatty acids to the tissue. Our aim was to evaluate the relations between LPL activity, regulators of LPL, and ceramides in EAT from CAD patients. We studied patients undergoing coronary bypass graft (CAD, n=25) and patients without CAD (no CAD, n=14). EAT and subcutaneous AT (SAT) were obtained, tissue LPL activity and its regulator's expression (ANGPTL4, GPIHBP1 [glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1], and PPARγ [peroxisomal proliferator-activated receptor γ]) were assessed. Tissue lipidomes were evaluated by UHPLC-MS, in positive and negative ionization modes. LPL activity was higher in EAT from CAD (P<0.001), and in EAT than SAT in both groups (P<0.001). ANGPTL4 levels were lower, GPIHBP1 and PPARγ levels were higher in EAT from CAD (P<0.001). In both groups, EAT exhibited more ceramide (P=0.01), directly associated with LPL activity, being the strongest association with Cer18:1/24:1 (P<0.001). EAT Cer18:1/16:0 to Cer18:1/24:0 and Cer18:1/24:1 to 18:1/24:0 ratios were higher in CAD (P=0.03; P<0.001, respectively), the latter directly associated with LPL activity (r=0.63, P<0.001) GPIHBP1 levels (r=0.68, P<0.001), and inversely to EAT ANGPTL4 expression (r=-0.49, P=0.03). Pairwise partial correlation network showed associations among bioactive lipids and LPL and its regulators (P<0.001 in all cases). The association between LPL activity, total ceramide, and the atherogenic ceramide ratios highlights the importance of the enzyme and these bioactive lipids contributing to the different metabolic profile of EAT in CAD.

Angiopoietin-like 4 governs diurnal lipoprotein lipase activity in brown adipose tissue

ObjectiveBrown adipose tissue (BAT) burns fatty acids (FAs) to produce heat, and shows diurnal oscillation in glucose and triglyceride (TG)-derived FA-uptake, peaking around wakening. Here we aimed to gain insight in the diurnal regulation of metabolic BAT activity. MethodsRNA-sequencing, chromatin immunoprecipitation (ChIP)-sequencing, and lipidomics analyses were performed on BAT samples of wild type C57BL/6J mice collected at 3-hour intervals throughout the day. Knockout and overexpression models were used to study causal relationships in diurnal lipid handling by BAT. ResultsWe identified pronounced enrichment of oscillating genes involved in extracellular lipolysis in BAT, accompanied by oscillations of FA and monoacylglycerol content. This coincided with peak lipoprotein lipase (Lpl) expression, and was predicted to be driven by peroxisome proliferator-activated receptor gamma (PPARγ) activity. ChIP-sequencing for PPARγ confirmed oscillation in binding of PPARγ to Lpl. Of the known LPL-modulators, angiopoietin-like 4 (Angptl4) showed the largest diurnal amplitude opposite to Lpl, and both Angptl4 knockout and overexpression attenuated oscillations of LPL activity and TG-derived FA-uptake by BAT. ConclusionsOur findings highlight involvement of PPARγ and a crucial role of ANGPTL4 in mediating the diurnal oscillation of TG-derived FA-uptake by BAT, and imply that time of day is essential when targeting LPL activity in BAT to improve metabolic health.

Angiopoietin-like proteins and postprandial partitioning of fatty acids.

Over the last two decades, evolving discoveries around angiopoietin-like (ANGPTL) proteins, particularly ANGPTL3, ANGPTL4, and ANGPTL8, have generated significant interest in understanding their roles in fatty acid (FA) metabolism. Until recently, exactly how this protein family regulates lipoprotein lipase (LPL) in a tissue-specific manner to control FA partitioning has remained elusive. This review summarizes the latest insights into mechanisms by which ANGPTL3/4/8 proteins regulate postprandial FA partitioning. Accumulating evidence suggests that ANGPTL8 is an insulin-responsive protein that regulates ANGPTL3 and ANGPTL4 by forming complexes with them to increase or decrease markedly their respective LPL-inhibitory activities. After feeding, when insulin levels are high, ANGPTL3/8 secreted by hepatocytes acts in an endocrine manner to inhibit LPL in skeletal muscle, whereas ANGPTL4/8 secreted by adipocytes acts locally to preserve adipose tissue LPL activity, thus shifting FA toward the fat for storage. Insulin also decreases hepatic secretion of the endogenous ANGPTL3/8 inhibitor, apolipoprotein A5 (ApoA5), to accentuate ANGPTL3/8-mediated LPL inhibition in skeletal muscle. The ANGPTL3/4/8 protein family and ApoA5 play critical roles in directing FA toward adipose tissue postprandially. Selective targeting of these proteins holds significant promise for the treatment of dyslipidemias, metabolic syndrome, and their related comorbidities.

Influence of Dietary Chitosan Feeding Duration on Glucose and Lipid Metabolism in a Diabetic Rat Model.

This study was designed to investigate the influence of dietary chitosan feeding-duration on glucose and lipid metabolism in diabetic rats induced by streptozotocin and nicotinamide [a non-insulin-dependent diabetes mellitus (NIDDM) model]. Male Sprague-Dawley rats were used as experimental animals and divided into short-term (6 weeks) and long-term (11 weeks) feeding durations, and each duration contained five groups: (1) control, (2) control + 5% chitosan, (3) diabetes, (4) diabetes + 0.8 mg/kg rosiglitazone (a positive control), and (5) diabetes + 5% chitosan. Whether the chitosan feeding was for 6 or 11 weeks, the chitosan supplementation decreased blood glucose and lipids levels and liver lipid accumulation. However, chitosan supplementation decreased plasma tumor necrosis factor (TNF)-α, insulin levels, alanine aminotransferase (ALT) activity, insulin resistance (HOMA-IR), and adipose tissue lipoprotein lipase activity. Meanwhile, it increased plasma high-density lipoproteins (HDL)-cholesterol level, plasma angiopoietin-like-4 protein expression, and plasma triglyceride levels (at 11-week feeding duration only). Taken together, 11-week (long-term) chitosan feeding may help to ameliorate the glucose and lipid metabolism in a NIDDM diabetic rat model.

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.

Real-time imaging of vascular brown adipose tissue lipoprotein lipase activity

Background and Aims: Lipoprotein lipase (LPL) liberates fatty acids and glycerol from the core of triglyceride-rich lipoproteins (TRLs). Delayed postprandial clearance of TRLs is associated with atherosclerosis. Measurement of the effective tissue LPL activity has proven difficult, as not only the intrinsic activity of the enzyme but also the intravascular localization is important for proper TRL processing. We developed an ultrafast confocal in vivo microscopy-based approach for visualizing LPL action in capillaries.

Fasting induces ANGPTL4 and reduces LPL activity in human adipose tissue

ObjectiveStudies in mice have shown that the decrease in lipoprotein lipase (LPL) activity in adipose tissue upon fasting is mediated by induction of the inhibitor ANGPTL4. Here, we aimed to validate this concept in humans by determining the effect of a prolonged fast on ANGPTL4 and LPL gene and protein expression in human subcutaneous adipose tissue. MethodsTwenty-three volunteers ate a standardized meal at 18.00 h and fasted until 20.00 h the next day. Blood was drawn and periumbilical adipose tissue biopsies were collected 2 h and 26 h after the meal. ResultsConsistent with previous mouse data, LPL activity in human adipose tissue was significantly decreased by fasting (−60%), concurrent with increased ANGPTL4 mRNA (+90%) and decreased ANGPTL8 mRNA (−94%). ANGPTL4 protein levels in adipose tissue were also significantly increased by fasting (+46%), whereas LPL mRNA and protein levels remained unchanged. In agreement with the adipose tissue data, plasma ANGPTL4 levels increased upon fasting (+100%), whereas plasma ANGPTL8 decreased (−79%). Insulin, levels of which significantly decreased upon fasting, downregulated ANGPTL4 mRNA and protein in primary human adipocytes. By contrast, cortisol, levels of which significantly increased upon fasting, upregulated ANGPTL4 mRNA and protein in primary human adipocytes as did fatty acids. ConclusionANGPTL4 levels in human adipose tissue are increased by fasting, likely via increased plasma cortisol and free fatty acids and decreased plasma insulin, resulting in decreased LPL activity.This clinical trial was registered with identifier NCT03757767.

Unfolding of monomeric lipoprotein lipase by ANGPTL4: Insight into the regulation of plasma triglyceride metabolism

The binding of lipoprotein lipase (LPL) to GPIHBP1 focuses the intravascular hydrolysis of triglyceride-rich lipoproteins on the surface of capillary endothelial cells. This process provides essential lipid nutrients for vital tissues (e.g., heart, skeletal muscle, and adipose tissue). Deficiencies in either LPL or GPIHBP1 impair triglyceride hydrolysis, resulting in severe hypertriglyceridemia. The activity of LPL in tissues is regulated by angiopoietin-like proteins 3, 4, and 8 (ANGPTL). Dogma has held that these ANGPTLs inactivate LPL by converting LPL homodimers into monomers, rendering them highly susceptible to spontaneous unfolding and loss of enzymatic activity. Here, we show that binding of an LPL-specific monoclonal antibody (5D2) to the tryptophan-rich lipid-binding loop in the carboxyl terminus of LPL prevents homodimer formation and forces LPL into a monomeric state. Of note, 5D2-bound LPL monomers are as stable as LPL homodimers (i.e., they are not more prone to unfolding), but they remain highly susceptible to ANGPTL4-catalyzed unfolding and inactivation. Binding of GPIHBP1 to LPL alone or to 5D2-bound LPL counteracts ANGPTL4-mediated unfolding of LPL. In conclusion, ANGPTL4-mediated inactivation of LPL, accomplished by catalyzing the unfolding of LPL, does not require the conversion of LPL homodimers into monomers. Thus, our findings necessitate changes to long-standing dogma on mechanisms for LPL inactivation by ANGPTL proteins. At the same time, our findings align well with insights into LPL function from the recent crystal structure of the LPL•GPIHBP1 complex.

Gochujang prepared using rice and wheat koji partially alleviates high-fat diet-induced obesity in rats.

The aim of this study was to compare whether gochujang products prepared using giant embryo rice koji (rice gochujang, RG) and wheat koji (wheat gochujang, WG) have anti‐obesity effects on rats fed a high‐fat diet (HFD), who served as a model for obesity. The nutritional composition of RG and WG including proximate constituents, amino acid and fatty acid compositions were investigated. Consequently, the secondary fermented metabolites were analyzed in RG and WG by ultrahigh‐performance liquid chromatography and mass spectrometry. Rats were fed a HFD containing 10% RG powder (HFD‐RG) or 10% WG powder (HFD‐WG) for 8 weeks. Body weight gain, weights of liver, epididymal, retroperitoneal, perirenal, and total white fat pads, and levels of serum triglyceride (TG), total cholesterol, low‐density lipoprotein cholesterol, and leptin were lower in all gochujang groups than in the HFD group. Furthermore, RG and WG treatment decreased the hepatic TG content and lipid accumulation and significantly reduced the size of epididymal adipocytes. These effects are probably mediated through inhibition of hepatic fatty acid synthase, acetyl CoA carboxylase, malic enzyme, and adipose tissue lipoprotein lipase activities. The anti‐obesity effect was slightly greater in the HFD‐RG group than in the HFD‐WG group. This effect may be attributed to secondary metabolites, such as capsaicin, genistein, daidzein, soyasaponin, and lysophosphatidylcholines, contained in gochujang prepared using giant embryo rice or wheat koji.

Effect of mountain ultra-marathon running on plasma angiopoietin-like protein 4 and lipid profile in healthy trained men

PurposeAngiopoietin-like protein 4 (ANGPTL4) regulates lipid metabolism by inhibiting lipoprotein lipase activity and stimulating lipolysis in adipose tissue. The aim of this study was to find out whether the mountain ultra-marathon running influences plasma ANGPTL4 and whether it is related to plasma lipid changes.MethodsTen healthy men (age 31 ± 1.1 years) completed a 100-km ultra-marathon running. Plasma ANGPTL4, free fatty acids (FFA), triacylglycerols (TG), glycerol (Gly), total cholesterol (TC), low (LDL-C) and high (HDL-C) density lipoprotein-cholesterol were determined before, immediately after the run and after 90 min of recovery.ResultsPlasma ANGPTL4 increased during exercise from 68.0 ± 16.5 to 101.2 ± 18.1 ng/ml (p < 0.001). This was accompanied by significant increases in plasma FFA, Gly, HDL-C and decreases in plasma TG concentrations (p < 0.01). After 90 min of recovery, plasma ANGPTL4 and TG did not differ significantly from the exercise values, while plasma FFA, Gly, TC and HDL-C were significantly lower than immediately after the run.TC/HDL-C and TG/HDL-C molar ratios were significantly reduced. The exercise-induced changes in plasma ANGPTL4 correlated positively with those of FFA (r = 0.73; p < 0.02), and HDL-C (r = 0.69; p < 0.05). Positive correlation was found also between plasma ANGPTL4 and FFA concentrations after 90 min of recovery (r = 0.77; p < 0.01).ConclusionsThe present data suggest that increase in plasma FFA during mountain ultra-marathon run may be involved in plasma ANGPTL4 release and that increase in ANGPTL4 secretion may be a compensatory mechanism against fatty acid-induced oxidative stress. Increase in plasma HDL-C observed immediately after the run may be due to the protective effect of ANGPTL4 on HDL.

The Anti-Obesity Effect of Polysaccharide-Rich Red Algae (Gelidium amansii) Hot-Water Extracts in High-Fat Diet-Induced Obese Hamsters.

This study investigated the anti-obesity effect of a polysaccharide-rich red algae Gelidium amansii hot-water extract (GHE) in high-fat (HF) diet-induced obese hamsters. GHE contained 68.54% water-soluble indigestible carbohydrate polymers. Hamsters were fed with a HF diet for 5 weeks to induce obesity, and then randomly divided into: HF group, HF with 3% guar gum diet group, HF with 3% GHE diet group, and HF with orlistat (200 mg/kg diet) group for 9 weeks. The increased weights of body, liver, and adipose in the HF group were significantly reversed by GHE supplementation. Lower plasma leptin, tumor necrosis factor-α, and interleukin-6 levels were observed in the GHE+HF group compared to the HF group. GHE also increased the lipolysis rate and decreased the lipoprotein lipase activity in adipose tissues. GHE induced an increase in the phosphorylation of AMP-activated protein kinase (AMPK) and the protein expressions of peroxisome proliferator-activated receptor alpha (PPARα) and uncoupling protein (UCP)-2 in the livers. The decreased triglyceride and total cholesterol in the plasma and liver were also observed in obese hamsters fed a diet with GHE. These results suggest that GHE exerts a down-regulation effect on hepatic lipid metabolism through AMPK phosphorylation and up-regulation of PPARα and UCP-2 in HF-induced obese hamsters.

ApoC-III ASO promotes tissue LPL activity in the absence of apoE-mediated TRL clearance

Hypertriglyceridemia results from accumulation of triglyceride (TG)-rich lipoproteins (TRLs) in the circulation and is associated with increased CVD risk. ApoC-III is an apolipoprotein on TRLs and a prominent negative regulator of TG catabolism. We recently established that in vivo apoC-III predominantly inhibits LDL receptor-mediated and LDL receptor-related protein 1-mediated hepatic TRL clearance and that apoC-III-enriched TRLs are preferentially cleared by syndecan-1 (SDC1). In this study, we determined the impact of apoE, a common ligand for all three receptors, on apoC-III metabolism using apoC-III antisense oligonucleotide (ASO) treatment in mice lacking apoE and functional SDC1 (Apoe−/−Ndst1f/fAlb-Cre+). ApoC-III ASO treatment significantly reduced plasma TG levels in Apoe−/−Ndst1f/fAlb-Cre+ mice without reducing hepatic VLDL production or improving hepatic TRL clearance. Further analysis revealed that apoC-III ASO treatment lowered plasma TGs in Apoe−/−Ndst1f/fAlb-Cre+ mice, which was associated with increased LPL activity in white adipose tissue in the fed state. Finally, clinical data confirmed that ASO-mediated lowering of APOC-III via volanesorsen can reduce plasma TG levels independent of the APOE isoform genotype. Our data indicate that apoE determines the metabolic impact of apoC-III as we establish that apoE is essential to mediate inhibition of TRL clearance by apoC-III and that, in the absence of functional apoE, apoC-III inhibits tissue LPL activity.

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.

Effect of Conjugated Linoleic Acids on Nutritional Status and Lipid Metabolism in Rats Fed Linoleic‐Acid‐Deprived Diets

This study aims to investigate the effect of conjugated linoleic acid (CLA) on nutritional parameters and triacylglycerol (TAG) regulation in male Wistar rats fed linoleic acid (LA)‐deprived (−LA) diets compared to LA‐enriched (+LA) diets. In both +LA and −LA groups, CLA are incorporated into the tissues, showing higher levels in the adipose tissue. However, different metabolic and nutritional effects are observed depending on the LA status. CLA markedly reduces fat depots in the −LA group, associated with an increased lipoprotein lipase (LPL) and lipogenic enzyme activities as compensatory mechanisms. Moreover, CLA restores the hepatic TAG levels in −LA animals, associated with a normalized triacylglycerol‐secretion rate (TAG‐SR), an increased lipogenic enzyme activity and higher mRNA levels of fatty acid synthase. Serum TAG levels are not affected by CLA in the +LA group. However, in the −LA group, CLA decreases the TAG levels associated with a reduced TAG‐SR and a higher adipose tissue LPL activity. Thus, the CLA effects on the nutritional parameters and TAG metabolism differs depending on the LA status. CLA causes certain beneficial biological and nutritional effects in LA‐deprived but not in LA‐enriched animals.Practical Applications: The approach by the authors involve growing animals in healthy physiological conditions fed with diets containing recommended levels of dietary fats, moderate amounts of commercial CLA mixture obtained from industrial synthesis (equimolecular amounts of 9c,11t‐ and 10t,12c‐isomers), and unbalanced LA levels. These variables constitute a situation observed in the human population. The present study might contribute to understanding the role of CLA on nutritional parameters and TAG metabolism depending on the nutritional milieu.Conjugated linoleic acid effects on nutritional parameters and triacylglycerol metabolism in rats fed linoleic‐acid‐enriched and linoleic‐acid‐deprived diets are determined.