Adipose Lipoprotein Lipase Research Articles

Postprandial exercise regulates tissue-specific triglyceride uptake through angiopoietin-like proteins.

Fuel substrate switching between carbohydrates and fat is essential for maintaining metabolic homeostasis. During aerobic exercise, the predominant energy source gradually shifts from carbohydrates to fat. While it is well known that exercise mobilizes fat storage from adipose tissues, it remains largely obscure how circulating lipids are distributed tissue-specifically according to distinct energy requirements. Here, we demonstrate that aerobic exercise is linked to nutrient availability to regulate tissue-specific activities of lipoprotein lipase (LPL), the key enzyme catabolizing circulating triglyceride (TG) for tissue uptake, through the differential actions of angiopoietin-like (ANGPTL) proteins. Exercise reduced the tissue binding of ANGPTL3 protein, increasing LPL activity and TG uptake in the heart and skeletal muscle in the postprandial state specifically. Mechanistically, exercise suppressed insulin secretion, attenuating hepatic Angptl8 transcription through the PI3K/mTOR/CEBPα pathway, which is imperative for the tissue binding of its partner ANGPTL3. Constitutive expression of ANGPTL8 hampered lipid utilization and resulted in cardiac dysfunction in response to exercise. Conversely, exercise promoted the expression of ANGPTL4 in white adipose tissues, overriding the regulatory actions of ANGPTL8/ANGPTL3 in suppressing adipose LPL activity, thereby diverting circulating TG away from storage. Collectively, our findings show an overlooked bifurcated ANGPTL-LPL network that orchestrates fuel switching in response to aerobic exercise.

Downregulation of adipose LPL by PAR2 contributes to the development of hypertriglyceridemia.

Lipoprotein lipase (LPL) hydrolyzes circulating triglycerides (TGs), releasing fatty acids (FA) and promoting lipid storage in white adipose tissue (WAT). However, the mechanisms regulating adipose LPL and its relationship with the development of hypertriglyceridemia are largely unknown. WAT from obese humans exhibited high PAR2 expression, which was inversely correlated with the LPL gene. Decreased LPL expression was also inversely correlated with elevated plasma TG levels, suggesting that adipose PAR2 might regulate hypertriglyceridemia by downregulating LPL. In mice, aging and high palmitic acid diet (PD) increased PAR2 expression in WAT, which was associated with a high level of macrophage migration inhibitory factor (MIF). MIF downregulated LPL expression and activity in adipocytes by binding with CXCR2/4 receptors and inhibiting Akt phosphorylation. In a MIF overexpression model, high-circulating MIF levels suppressed adipose LPL, and this suppression was associated with increased plasma TGs but not FA. Following PD feeding, adipose LPL expression and activity were significantly reduced, and this reduction was reversed in Par2-/- mice. Recombinant MIF infusion restored high plasma MIF levels in Par2-/- mice, and the levels decreased LPL and attenuated adipocyte lipid storage, leading to hypertriglyceridemia. These data collectively suggest that downregulation of adipose LPL by PAR2/MIF may contribute to the development of hypertriglyceridemia.

6-OR: PAR2 Downregulates Adipose LPL through MIF—A Novel Adipose Mechanism Contributing to the Development of Hypertriglyceridemia

Lipoprotein lipase (LPL) is a key enzyme that hydrolyzes circulating triglycerides to release fatty acid (FA). In adipose tissue, LPL is required for lipid storage. However, it is currently unknown whether alteration of LPL in white adipose tissue (WAT) contributes to the development of hypertriglyceridemia. Our present study indicated that WAT isolated from human obese patients have increased expression of PAR2 which is negatively associated with LPL gene. The reduced LPL expression is also negatively correlated with increased plasma TG levels, suggesting that adipose PAR2 may modulate hyperlipidemia through downregulating LPL. In mice, aging and high palmitic oil diet significantly increased PAR2 expression in adipose tissue which was associated with high plasma MIF levels. PAR2 deficiency attenuates the rise of MIF, suggesting a key role of PAR2 in regulating adipose MIF release. MIF reduced LPL expression and activity in adipocytes. In a MIF overexpressed animal model (Mif lung Tg), high circulating MIF levels inhibited adipose LPL which was associated with increased plasma triglyceride but not fatty acid. Following high palmitic oil diet feeding, adipose LPL expression and activity were also reduced, and this reduction was reversed in PAR2 knockout mice. Interestingly, PAR2 mediated LPL in adipose tissue regulates hypertriglyceridemia through controlling adipocyte lipid storage. In Par2-/- mice, recombinant MIF perfusion recovered high plasma MIF levels, which decreased LPL and attenuated adipocyte lipid storage leading to hypertriglyceridemia. These data together suggest that the downregulation of adipose LPL by PAR2/MIF is an important mechanism for the development of hypertriglyceridemia. Disclosure Y.Huang: None. L.Li: None. L.Chen: None. X.Chen: None. P.Gao: None. Y.Qi: None. D.Qi: None. Funding Canadian Institutes of Health Research (PJT156116)

Effect of Cold Exposure and Exercise on Insulin Sensitivity and Serum Free Fatty Acids in Obese Rats.

This study aimed to explore the effect of exercise and cold exposure on insulin sensitivity and the level of serum free fatty acids (FFA) in diet-induced obese rats. Sixty-four diet-induced obese rats were randomly assigned to eight groups: room temperature-sedentary, room temperature-exercise, acute cold exposure-sedentary, acute cold exposure-exercise, intermittent cold exposure-sedentary, intermittent cold exposure-exercise, sustained cold exposure-sedentary, and sustained cold exposure-exercise. After the interventions, the homeostatic model assessment for insulin resistance (HOMA-IR) values, the level of serum FFA, subcutaneous fat ratio (SFR) and visceral fat ratio, enzyme activities of adipose triglyceride lipase, and lipoprotein lipase (LPL) in inguinal adipose tissue, and protein expression of PGC1-α and p38 MAPK in skeletal muscle were investigated. We found that exercise ( P = 0.0136) and cold exposure ( P < 0.0001) reduced HOMA-IR values independently. Exercise reduced serum FFA ( P = 0.0041), whereas cold exposure did not affect them. Moreover, the HOMA-IR values were positively correlated with the serum FFA levels ( r = 0.32, P = 0.01). SFR or visceral fat ratio was coordinately reduced by the interaction (for SFR, P = 0.0015) or opposing main effects between or of cold exposure and exercise, supporting the reduction of serum FFA. However, cold exposure or exercise increased the activity of adipose triglyceride lipase and LPL independently or interactively (for LPL, P = 0.0143), suggesting an increase in serum FFA. Finally, cold exposure and exercise enhanced protein expression of PGC1-α and p38 MAPK independently or interactively (for p38 MAPK, P = 0.0226), suggesting increased uptake and oxidation of serum FFA in muscle. These results suggest that the combination of exercise and cold exposure may result in more serum FFA utilization than production and thus lead to reduced serum FFA and increased insulin sensitivity.

SGIV Induced and Exploited Cellular De Novo Fatty Acid Synthesis for Virus Entry and Replication.

Considerable attention has been paid to the roles of lipid metabolism in virus infection due to its regulatory effects on virus replication and host antiviral immune response. However, few literature has focused on whether lipid metabolism is involved in the life cycle of lower vertebrate viruses. Singapore grouper iridovirus (SGIV) is the causative aquatic virus that extensively causes fry and adult groupers death. Here, the potential roles of cellular de novo fatty acid synthesis in SGIV infection was investigated. SGIV infection not only increased the expression levels of key enzymes in fatty acid synthesis in vivo/vitro, including acetyl-Coenzyme A carboxylase alpha (ACC1), fatty acid synthase (FASN), medium-chain acyl-CoA dehydrogenase (MCAD), adipose triglyceride lipase (ATGL), lipoprotein lipase (LPL) and sterol regulatory element-binding protein-1 (SREBP1), but it also induced the formation of lipid droplets (LDs), suggesting that SGIV altered de novo fatty acid synthesis in host cells. Using the inhibitor and specific siRNA of ACC1 and FASN, we found that fatty acid synthesis was essential for SGIV replication, evidenced by their inhibitory effects on CPE progression, viral gene transcription, protein expression and virus production. Moreover, the inhibitor of fatty acid β-oxidation could also reduce SGIV replication. Inhibition of fatty acid synthesis but not β-oxidation markedly blocked virus entry during the life cycle of SGIV infection. In addition, we also found that inhibition of ACC1 and FASN increased the IFN immune and inflammatory response during SGIV infection. Together, our data demonstrated that SGIV infection in vitro regulated host lipid metabolism and, in that process, cellular fatty acid synthesis might exert crucial roles during SGIV infection via regulating virus entry and host immune response.

Abstract P112: A Simple, Rapid, And Sensitive Fluorescence-based Method To Assess Triacylglycerol Hydrolase Activities

Introduction: Lipases constitute an important class of water-soluble enzymes that catalyze the hydrolysis of hydrophobic triacylglycerol (TAG). Their activity is usually measured after isolation and quantification of the hydrolyzed free fatty acids. We have used NBD-labeled lipids previously to develop TAG, cholesteryl ester, and phospholipid transfer assays for microsomal triglyceride transfer protein. To date, however, NBD-labeled TAG (NBD-TAG) has not been used to assess the enzymatic activities of different lipases. Methods: We developed methods to measure lipase activities using adipose triglyceride lipase (ATGL), lipoprotein lipase (LpL), and pancreatic triglyceride lipase (PNLIP) as model lipases. In these assays, we incubated a source of ATGL, LpL, or PNLIP with substrate emulsions containing nitrobenzoxadiazole (NBD)-labeled TAG in phosphatidylcholine (PC) and phosphatidylinositol (PI), measured increases in NBD fluorescence with time, and calculated enzyme activities. Results: Incorporation of NBD-TAG into PC vesicles resulted in some hydrolysis; but required product isolation step to measure NBD fluorescence. However, incorporation of PI into these NBD-TAG/PC vesicles significantly increased substrate hydrolysis in time, protein, and substrate concentration dependent manner negating the need to isolate products to measure lipase activities. Further, increasing the ratio of NBD-TAG to PC enhanced substrate hydrolysis. Next, we tested specific lipase inhibitors and found that orlistat inhibits all three enzymes indicating that it is a pan-lipase inhibitor. Conclusions: We describe a simple, rapid fluorescence-based TAG hydrolysis assay to assess three major TAG hydrolases: ATGL localized intracellularly, LpL localized at the extracellular endothelium, and PNLIP produced and secreted from the pancreas into the intestinal lumen. The major advantages of this method are its speed, simplicity, and avoidance of a product isolation step. This assay is potentially applicable to a wide range of lipases and is amenable to high-throughput screening to discover novel modulators of triacylglycerol hydrolases, and in the diagnosis of diseases associated with increases in plasma lipase activities.

Regulation of plasma triglyceride partitioning by adipose-derived ANGPTL4 in mice

Elevated plasma triglyceride levels are associated with metabolic disease. Angiopoietin-like protein 4 (ANGPTL4) regulates plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). Our aim was to investigate the role of adipocyte-specific deficiency of ANGPTL4 in mice during high fat diet feeding. Adipocyte-specific ANGPTL4 deficient mice were fed a high fat diet (60% kCal from fat) for either 12 weeks or 6 months. We performed plasma metabolic measurements, triglyceride clearance and uptake assays, LPL activity assays, and assessed glucose homeostasis. Mice lacking adipocyte ANGPTL4 recapitulated the triglyceride phenotypes of whole-body ANGPTL4 deficiency, including increased adipose LPL activity, lower plasma triglyceride levels, and increased uptake of triglycerides into adipose tissue. When fed a high fat diet (HFD), these mice continued to display enhanced adipose LPL activity and initially had improved glucose and insulin sensitivity. However, after 6 months on HFD, the improvements in glucose homeostasis were largely lost. Moreover, despite higher adipose LPL activity levels, mice lacking adipocyte ANGPTL4 no longer had increased triglyceride uptake into adipose compared to littermate controls after chronic high-fat feeding. These observations suggest that after chronic high-fat feeding LPL is no longer rate-limiting for triglyceride delivery to adipocytes. We conclude that while adipocyte-derived ANGPTL4 is an important regulator of plasma triglyceride levels and triglyceride partitioning under normal diet conditions, its role is diminished after chronic high-fat feeding.

Lipoprotein Lipase Inhibitor, Nordihydroguaiaretic Acid, Aggravates Metabolic Phenotypes and Alters HDL Particle Size in the Western Diet-Fed db/db Mice.

Lipoprotein lipase (LPL) hydrolyzes triglycerides in lipoprotein to supply fatty acids, and its deficiency leads to hypertriglyceridemia, thereby inducing metabolic syndrome (MetSyn). Nordihydroguaiaretic acid (NDGA) has been recently reported to inhibit LPL secretion by endoplasmic reticulum (ER)-Golgi redistribution. However, the role of NDGA on dyslipidemia and MetSyn remains unclear. To address this question, leptin receptor knock out (KO)-db/db mice were randomly assigned to three different groups: A normal AIN76-A diet (CON), a Western diet (WD) and a Western diet with 0.1% NDGA and an LPL inhibitor, (WD+NDGA). All mice were fed for 12 weeks. The LPL inhibition by NDGA was confirmed by measuring the systemic LPL mass and adipose LPL gene expression. We investigated whether the LPL inhibition by NDGA alters the metabolic phenotypes. NDGA led to hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. More strikingly, the supplementation of NDGA increased the percentage of high density lipoprotein (HDL)small (HDL3a+3b+3c) and decreased the percentage of HDLlarge (HDL2a+2b) compared to the WD group, which indicates that LPL inhibition modulates HDL subclasses. was NDGA increased adipose inflammation but had no impact on hepatic stress signals. Taken together, these findings demonstrated that LPL inhibition by NDGA aggravates metabolic parameters and alters HDL particle size.

Human hepatic lipase overexpression in mice induces hepatic steatosis and obesity through promoting hepatic lipogenesis and white adipose tissue lipolysis and fatty acid uptake.

Human hepatic lipase (hHL) is mainly localized on the hepatocyte cell surface where it hydrolyzes lipids from remnant lipoproteins and high density lipoproteins and promotes their hepatic selective uptake. Furthermore, hepatic lipase (HL) is closely associated with obesity in multiple studies. Therefore, HL may play a key role on lipid homeostasis in liver and white adipose tissue (WAT). In the present study, we aimed to evaluate the effects of hHL expression on hepatic and white adipose triglyceride metabolism in vivo. Experiments were carried out in hHL transgenic and wild-type mice fed a Western-type diet. Triglyceride metabolism studies included β-oxidation and de novo lipogenesis in liver and WAT, hepatic triglyceride secretion, and adipose lipoprotein lipase (LPL)-mediated free fatty acid (FFA) lipolysis and influx. The expression of hHL promoted hepatic triglyceride accumulation and de novo lipogenesis without affecting triglyceride secretion, and this was associated with an upregulation of Srebf1 as well as the main genes controlling the synthesis of fatty acids. Transgenic mice also exhibited more adiposity and an increased LPL-mediated FFA influx into the WAT without affecting glucose tolerance. Our results demonstrate that hHL promoted hepatic steatosis in mice mainly by upregulating de novo lipogenesis. HL also upregulated WAT LPL and promoted triglyceride-rich lipoprotein hydrolysis and adipose FFA uptake. These data support the important role of hHL in regulating hepatic lipid homeostasis and confirm the broad cardiometabolic role of HL.

ANGPTL3 is part of the machinery causing dyslipidemia majorily via LPL inhibition in mastitis mice

Previous investigations have shown that inflammation induces changes in lipid and lipoprotein metabolism, and increased expression of angiopoietin-like protein 3 (ANGPTL3) contributes to the development of dyslipidemia. Here we investigated whether there is a correlation between increased ANGPTL3 expression and dyslipidemia in mastitis mice. Thirty mice were divided into two groups: control group and Staphylococcus aureus (S. aureus)–induced mastitis mice group. Changes in the levels of blood lipids [total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C)]; activity of myeloperoxidase (MPO); concentrations of plasma inflammation biomarkers [interferon-γ (IFNγ), tumor necrosis factor α (TNFα), and interleukin-1α (IL-1α)]; concentration of plasma ANGPTL3 protein; lipoprotein lipase (LPL) activities in postheparin plasma; expressions of hepatic N-acetylgalactosaminyltransferase 2 (GALNT2), hepatic ANGPTL3 and adipose LPL were determined. The major results indicated specific pathological mammary tissue changes, elevated MPO activity, reduced GALNT2 mRNA expression, elevated ANGPTL3 mRNA and protein expression and reduced LPL mRNA and protein expression. In plasma samples the S.aureus infused mice displayed elevated ANGPTL3 protein concentration, TG, TC and LDL-C levels, and reduced postheparin LPL activities and HDL-C level. The data suggests that ANGPTL3 is part of the machinery causing dyslipidemia majorily via LPL inhibition in mastitis mice.

A hepatic amino acid/mTOR/S6K-dependent signalling pathway modulates systemic lipid metabolism via neuronal signals

Metabolism is coordinated among tissues and organs via neuronal signals. Levels of circulating amino acids (AAs), which are elevated in obesity, activate the intracellular target of rapamycin complex-1 (mTORC1)/S6kinase (S6K) pathway in the liver. Here we demonstrate that hepatic AA/mTORC1/S6K signalling modulates systemic lipid metabolism via a mechanism involving neuronal inter-tissue communication. Hepatic expression of an AA transporter, SNAT2, activates the mTORC1/S6K pathway, and markedly elevates serum triglycerides (TGs), while downregulating adipose lipoprotein lipase (LPL). Hepatic Rheb or active-S6K expression have similar metabolic effects, whereas hepatic expression of dominant-negative-S6K inhibits TG elevation in SNAT2 mice. Denervation, pharmacological deafferentation and β-blocker administration suppress obesity-related hypertriglyceridemia with adipose LPL upregulation, suggesting that signals are transduced between liver and adipose tissue via a neuronal pathway consisting of afferent vagal and efferent sympathetic nerves. Thus, the neuronal mechanism uncovered here serves to coordinate amino acid and lipid levels and contributes to the development of obesity-related hypertriglyceridemia.

Chronic Intermittent Hypoxia Induces Atherosclerosis via Activation of Adipose Angiopoietin-like 4

Obstructive sleep apnea is a risk factor for dyslipidemia and atherosclerosis, which have been attributed to chronic intermittent hypoxia (CIH). Intermittent hypoxia inhibits a key enzyme of lipoprotein clearance, lipoprotein lipase, and up-regulates a lipoprotein lipase inhibitor, angiopoietin-like 4 (Angptl4), in adipose tissue. The effects and mechanisms of Angptl4 up-regulation in sleep apnea are unknown. To examine whether CIH induces dyslipidemia and atherosclerosis by increasing adipose Angptl4 via hypoxia-inducible factor-1 (HIF-1). ApoE(-/-) mice were exposed to intermittent hypoxia or air for 4 weeks while being treated with Angptl4-neutralizing antibody or vehicle. In vehicle-treated mice, hypoxia increased adipose Angptl4 levels, inhibited adipose lipoprotein lipase, increased fasting levels of plasma triglycerides and very low density lipoprotein cholesterol, and increased the size of atherosclerotic plaques. The effects of CIH were abolished by the antibody. Hypoxia-induced increases in plasma fasting triglycerides and adipose Angptl4 were not observed in mice with germline heterozygosity for a HIF-1α knockout allele. Transgenic overexpression of HIF-1α in adipose tissue led to dyslipidemia and increased levels of adipose Angptl4. In cultured adipocytes, constitutive expression of HIF-1α increased Angptl4 levels, which was abolished by siRNA. Finally, in obese patients undergoing bariatric surgery, the severity of nocturnal hypoxemia predicted Angptl4 levels in subcutaneous adipose tissue. HIF-1-mediated increase in adipose Angptl4 and the ensuing lipoprotein lipase inactivation may contribute to atherosclerosis in patients with sleep apnea.

Adipose-specific Lipoprotein Lipase Deficiency More Profoundly Affects Brown than White Fat Biology

Adipose fat storage is thought to require uptake of circulating triglyceride (TG)-derived fatty acids via lipoprotein lipase (LpL). To determine how LpL affects the biology of adipose tissue, we created adipose-specific LpL knock-out (ATLO) mice, and we compared them with whole body LpL knock-out mice rescued with muscle LpL expression (MCK/L0) and wild type (WT) mice. ATLO LpL mRNA and activity were reduced, respectively, 75 and 70% in gonadal adipose tissue (GAT), 90 and 80% in subcutaneous tissue, and 84 and 85% in brown adipose tissue (BAT). ATLO mice had increased plasma TG levels associated with reduced chylomicron TG uptake into BAT and lung. ATLO BAT, but not GAT, had altered TG composition. GAT from MCK/L0 was smaller and contained less polyunsaturated fatty acids in TG, although GAT from ATLO was normal unless LpL was overexpressed in muscle. High fat diet feeding led to less adipose in MCK/L0 mice but TG acyl composition in subcutaneous tissue and BAT reverted to that of WT. Therefore, adipocyte LpL in BAT modulates plasma lipoprotein clearance, and the greater metabolic activity of this depot makes its lipid composition more dependent on LpL-mediated uptake. Loss of adipose LpL reduces fat accumulation only if accompanied by greater LpL activity in muscle. These data support the role of LpL as the "gatekeeper" for tissue lipid distribution.

Effect of chronic intermittent hypoxia on triglyceride uptake in different tissues

Chronic intermittent hypoxia (CIH) inhibits plasma lipoprotein clearance and adipose lipoprotein lipase (LPL) activity in association with upregulation of an LPL inhibitor angiopoietin-like protein 4 (Angptl4). We hypothesize that CIH inhibits triglyceride (TG) uptake via Angptl4 and that an anti-Angptl4-neutralizing antibody would abolish the effects of CIH. Male C57BL/6J mice were exposed to four weeks of CIH or intermittent air (IA) while treated with Ab (30 mg/kg ip once a week). TG clearance was assessed by [H(3)]triolein administration retroorbitally. CIH delayed TG clearance and suppressed TG uptake and LPL activity in all white adipose tissue depots, brown adipose tissue, and lungs, whereas heart, liver, and spleen were not affected. CD146+ CD11b- pulmonary microvascular endothelial cells were responsible for TG uptake in the lungs and its inhibition by CIH. Antibody to Angptl4 decreased plasma TG levels and increased TG clearance and uptake into adipose tissue and lungs in both control and CIH mice to a similar extent, but did not reverse the effects of CIH. The antibody reversed the effects of CIH on LPL in adipose tissue and lungs. In conclusion, CIH inactivates LPL by upregulating Angptl4, but inhibition of TG uptake occurs predominantly via an Angptl4/LPL-independent mechanism.

Human skeletal muscle perilipin 2 and 3 expression varies with insulin sensitivity

Background: Impaired insulin sensitivity may partly arise from a dysregulated lipid metabolism in human skeletal muscle. This study investigates the expression levels of perilipin 2, 3, and 5, and four key lipases in human skeletal muscle from the subjects that exhibit a range from normal to very low insulin sensitivity. Methods: 25 middle aged male participants were matched for lean body mass and recruited into three groups; type 2 diabetes patients (T2D), impaired glucose tolerance (IGT), and healthy sedentary controls (CON) according to their glucose tolerance and VO2peak. A muscle biopsy was obtained from vastus lateralis, and a two-step sequential euglycaemic-hyperinsulinaemic clamp was performed. Muscle samples were analyzed by Western blot for expression of perilipin 2, 3, 5, adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), endothelial lipase (EL) and lipoprotein lipase (LPL). Results: Perilipin 3 expression was higher in T2D compared to CON. Perilipin 2 expression was higher in CON than T2D. We observed no difference in expression of perili pin 5, ATGL, HSL, EL or LPL between the groups. Conclusions: In the present study the muscle perilipin 3 expression and perilipin 2 expression varied markedly with insulin sensitivity. This difference in perilipin expression may indicate that the lipid droplet function and thus storage and release of fatty acid-vary with insulin sensitivity.

Kaempferol improves carcase characteristics in broiler chickens by regulating ANGPTL3 gene expression

1. The objective of this study was to examine the beneficial effects of kaempferol, a naturally occurring polyphenol, on carcase characteristics in broiler chickens and the mechanisms involved in this regulation. 2. Broiler chickens were randomly divided into 7 groups: control, carrier control, kaempferol (0·3%), kaempferol (0·6%), hypercholesterolemic (HLD), HLD and kaempferol (0·3%), HLD and kaempferol (0·6%). 3. Seven weeks after treatment, carcase characteristics, lipid levels in the blood and liver, expression of hepatic Angiopoietin-like protein 3 (ANGPTL3) mRNA, and expression of adipose lipoprotein lipase (LPL) protein were determined. 4. Treatment with kaempferol (0·3 or 0·6%) significantly increased plasma high-density lipoprotein cholesterol levels, decreased percentage of abdominal fat, thickness of subcutaneous fat, plasma and hepatic total cholesterol and triglyceride concentrations, muscle malondialdehyde level and down-regulated expression of ANGPTL3 mRNA concomitantly with up-regulated expression of LPL protein in normal and hypercholesterolemic broiler chickens. 5. Kaempferol (0·3 or 0·6%) treatment had no significant effect on the values of percentage of breast muscle, percentage of leg muscle, carcase weight and eviscerated percentage. 6. The results suggest that kaempferol improves carcase characteristics by decreasing expression of ANGPTL3 in broiler chickens.

PPARγ2 Pro12Ala polymorphism is associated with improved lipoprotein lipase functioning in adipose tissue of insulin resistant obese women

Lipoprotein lipase (LPL) plays a pivotal role in lipid metabolism, contributes to metabolic disorders related to insulin action and body weight regulation, and is influenced by inflammation. The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR)γ2 gene seems to influence LPL functioning, but its role in obesity and insulin resistance status, which usually coexist in the clinical setting, has not been explored. Our aim was to analyze the association of obesity and insulin resistance with adipose LPL activity and expression, and the influence of the PPARγ2 Pro12Ala polymorphism. A cross-sectional study was conducted in 58 reproductive-age women who underwent elective abdominal surgery. Free-fatty acids, glucose, insulin, and selected adipokines were measured in fasting blood samples. DNA was isolated and the polymorphism genotyped. Biopsies of abdominal subcutaneous adipose tissue obtained during surgery were used to determine enzymatic LPL activity and expression; and expression of selected cytokines. Overweight/obese women presented lower LPL activity (P=0.022) and higher circulating TNF-α (P=0.020) than controls. Insulin resistant women also showed borderline lower LPL activity than non-resistant (P=0.052), but adiposity and inflammatory molecules were comparable. Nevertheless, LPL activity was higher in Pro12Ala carriers than in non-carriers after adjusting for obesity, insulin resistance and inflammation. Likewise, adipose LPL expression was increased in carriers while expression of cytokines was decreased. Our data suggest that insulin resistance is associated with low adipose LPL activity independently of obesity, but the PPARγ2 Pro12Ala polymorphism seems to protect the LPL functioning of obese insulin resistant women, likely through regulating inflammation in adipose tissue.

1,3,5,8-Tetrahydroxyxanthone regulates ANGPTL3–LPL pathway to lessen the ketosis in mice

Ketosis is a metabolic disorder closely associated with both lipid and carbohydrate metabolism. Recent studies show that angiopoietin-like protein 3 (ANGPTL3) contributes to the development of metabolic disorder. The objective of this study was to explore the inhibitory effect of 1,3,5,8-tetrahydroxyxanthone (Xan), a naturally occurring flavonoid compound, on ketosis and the mechanisms involved in this regulation. After 4weeks, Xan (10 or 30mg/kg, intragastrically) treatment decreased plasma total ketone bodies, malondialdehyde, 8-isoprostane, triglyceride, total cholesterol levels, and hepatic ANGPTL3 expression concomitantly with increased plasma glucose concentration and adipose lipoprotein lipase (LPL) expression in ketosis murine. The present results suggest that Xan regulates ANGPTL3–LPL pathway to lessen the ketosis in mice.

Acute Intermittent Hypoxia Inhibits Triglycerides Clearance And Has a Tissue‐Specific Effect on Lipoprotein Lipase Activity

Background We have recently shown that chronic intermittent hypoxia (IH) decreases triglycerides (TG) clearance due to the inhibition of lipoprotein lipase (LPL) activity in adipose tissue. However, the impact of acute IH on TG clearance and LpL activity remains unknown. Methods Male C57BL/6J mice were exposed to 7hs of IH with FiO2 decreasing from 20.9% to 5% once per minute or to intermittent air (IA). During the exposure, intralipid (20%, 7.5 ml/kg) was administered and serum triglyceride levels were measured over the 2 hr time course. In a separate batch of mice, fasting (5 hrs) LPL activity was measured in the epididymal fat pads, heart and skeletal muscle. Results Compared to IA, IH increased TG levels throughout the 2 hr time course of intralipid (p <0.01). Exposure to IH for 7 hrs resulted in a significant decrease in adipose LPL activity (IA: 5.83±0.51 vs. IH: 4.40±0.29 umol FFA released/g/hr; P<0.05) and a significant increase in the heart LPL activity (IA: 42.61±2.28 vs. IH: 60.70±3.05 umol FFA released/g/hr; P<0.01). No difference was observed in the skeletal muscle. Conclusions Acute IH inhibits TG clearance, possibly by suppressing adipose LpL activity. A simultaneous increase in heart LpL may be attributable to the heightened myocardial demand in fatty acids as a source of energy. Research Support: R01 HL80105, AHA 10GRNT3360001, 5P50HL084945, FAPESP 2010/11681-0

Decreased Protein Expression of Lipoprotein Lipase in Late Fasting Elephant Seals

During prolonged food deprivation, glycogen stores are depleted, and mammals rely on oxidation of fatty acids for energy. Thus, the breakdown of triglycerides (TG) becomes a critical process by which metabolic substrates become available to support energy requirements. Prolonged fasting is associated with the onset of insulin resistance so it should be expected that content of insulin-responsive enzymes such as lipoprotein lipase (LpL) which cleave TG would decrease resulting in decreased free fatty acids (FFA) and glycerol. Prolonged fasting in northern elephant seals is associated with decreased insulin but elevated FFA; the changes in LpL have not been examined. To address the hypothesis that LpL decreases in fasting seals, we measured adipose LpL in Early (n=9; 2–3 weeks post weaning) and Late (n=8; 6–8 weeks post weaning) fasted pups. LpL decreased (8%), but plasma FFA, glycerol and TG all increased 41%, 27% and 40%, respectively late in fast. This suggests that LpL does not contribute significantly to metabolism of TG in adipose of prolong-fasted seals. Increased TG may be necessary to provide sufficient substrate for increased lipolysis, resulting in increased FFA and glycerol. This pattern of substrate-product utilization suggests elephant seals have a robust mechanism to maintain TG levels to maintain energetic demands during their fast. This project was funded by NIH NCMHD 9T37MD001480 & P20MD005049.