Increased Lipoprotein Lipase Activity Research Articles

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.

Dose Effects of Ammonium Perfluorooctanoate on Lipoprotein Metabolism in APOE*3-Leiden.CETP Mice.

Epidemiological studies have reported positive associations between serum perfluorooctanoic acid (PFOA) and total and non-high-density lipoprotein cholesterol (non-HDL-C) although the magnitude of effect of PFOA on cholesterol lacks consistency. The objectives of this study were to evaluate the effect of PFOA on plasma cholesterol and triglyceride metabolism at various plasma PFOA concentrations relevant to humans, and to elucidate the mechanisms using APOE*3-Leiden.CETP mice, a model with a human-like lipoprotein metabolism. APOE*3-Leiden.CETP mice were fed a Western-type diet with PFOA (10, 300, 30 000 ng/g/d) for 4–6 weeks. PFOA exposure did not alter plasma lipids in the 10 and 300 ng/g/d dietary PFOA dose groups. At 30 000 ng/g/d, PFOA decreased plasma triglycerides (TG), total cholesterol (TC), and non-HDL-C, whereas HDL-C was increased. The plasma lipid alterations could be explained by decreased very low-density lipoprotein (VLDL) production and increased VLDL clearance by the liver through increased lipoprotein lipase activity. The concomitant increase in HDL-C was mediated by decreased cholesteryl ester transfer activity and changes in gene expression of proteins involved in HDL metabolism. Hepatic gene expression and pathway analysis confirmed the changes in lipoprotein metabolism that were mediated for a major part through activation of the peroxisome proliferator-activated receptor (PPAR)α. Our data confirmed the findings from a phase 1 clinical trial in humans that demonstrated high serum or plasma PFOA levels resulted in lower cholesterol levels. The study findings do not show an increase in cholesterol at environmental or occupational levels of PFOA exposure, thereby indicating these findings are associative rather than causal.

Abstract 167: Mechanism of Increased Low Density Lipoprotein Cholesterol and Decreased Triglycerides with Sodium-glucose Co-transporter 2 Inhibition

Objective: Although Sodium glucose cotransporter 2 (SGLT2) inhibition in humans sometimes leads to increased levels of low density lipoprotein (LDL) cholesterol, this therapy is associated with marked reduction in cardiovascular disease. In this study, we aimed to determine how SGLT2 inhibition alters circulating lipoproteins. Approach and Results: We used a mouse model in which plasma lipoprotein profiles were humanized by expression of human cholesteryl ester transfer protein and human apolipoprotein B100 to determine how SGLT2 inhibition alters lipoprotein profiles. The mice were fed a high fat diet and then were made partially insulin deficient using streptozotocin. SGLT2 was inhibited using a specific anti-sense oligonucleotide or canagliflozin, a clinically available oral SGLT2 inhibitor. Inhibition of SGLT2 increased circulating levels of LDL cholesterol and reduced plasma triglyceride levels. SGLT2 inhibition was associated with increased lipoprotein lipase activity in the post heparin plasma and decreased postprandial lipemia. The changes in lipoprotein metabolism were more significant in mice treated with SGLT2 ASO compared to canagliflozin. Conclusions: Our studies in mice recapitulate many of the changes in circulating lipids found with SGLT2 inhibition therapy in humans and suggest that the increased LDL cholesterol found with this therapy is due to greater lipolysis of triglyceride-rich lipoproteins. This change in lipoprotein physiology is likely, in part, to explain the reduced cardiovascular disease found with SGLT2 inhibition.

Triglyceride-lowering trials.

We provide an overview of current evidence about the independent role of high triglyceride levels for cardiovascular risk and for acute pancreatitis. Natural experiments of Mendelian randomization have given us a deeper understanding about the molecular pathways involved in triglyceride metabolism. Individuals with low-triglyceride levels generally have lower rates of cardiovascular disease (CVD). There has been a significant growth in the development of new agents that modulate enzymes involved in a variety of aspects of triglyceride packaging into VLDL or chylomicron particles, and triglyceride catabolism. Antisense inhibitors of apolipoprotein CIII are being tested, as are a variety of agents designed to increase lipoprotein lipase activity. Large-scale trials are underway with purified fatty acid (FA) formulations in over 20 000 individuals in aggregate. A large study of a new fibrate is underway. A focus on patients with elevated triglyceride levels is a new paradigm not previously the focus of large trials. Clinical outcome data on cardiovascular risk reductions remains sparse. Some drugs are already approved for use in rare inherited disorders predisposing to severe hypertriglyceridaemia and acute pancreatitis. Safety and costs issues are critical.

Lycopene amends LPS induced oxidative stress and hypertriglyceridemia via modulating PCSK-9 expression and Apo-CIII mediated lipoprotein lipase activity

This study was undertaken to uncover the regulatory role of lycopene in targeting lipopolysaccharide (LPS) induced oxidative stress and inflammatory cascades and subsequent regulation of proprotein convertase subtilisin/kexin type-9 (PCSK-9) expression via sterol regulatory element binding protein-2 (SREBP-2) and hepatocyte nuclear factor-1α (HNF-1α). Further, protein-protein interaction (PPI) studies for Lycopene-Apo-CIII complex against lipoprotein lipase (LPL) were also performed to assess its regulatory role behind the enhanced circulatory TG/TRLs clearance. Lycopene treatment down-regulated hepatocyte PCSK-9 expression via down-regulation of HNF-1α, whereas, LDL-receptor (LDL-R) was up-regulated by subsequent up-regulation of SREBP-2. PPI studies showed that lycopene diminishes the affinity of Apo-CIII to complex with LPL (ΔG: −917.1 Kcal/mol) resulting in increased LPL functionality and TRLs clearance. Moreover, lycopene also ameliorated LPS stimulated oxidative-stress via enhanced total antioxidant and HDL associated PON-1 activity in addition to down-regulate the expression and plasma level of inflammatory mediators. Based on above findings, we concluded that lycopene exhibits dual role in targeting LPS induced oxidative stress and hypertriglyceridemia via down-regulation of PCSK-9, making greater no. of surface LDL-R available for LPS processing and clearance, as well as increased LPL activity through inhibition of Apo-CIII.

ANGPTL8 promotes the ability of ANGPTL3 to bind and inhibit lipoprotein lipase

ObjectiveSeveral members of the angiopoietin-like (ANGPTL) family of proteins, including ANGPTL3 and ANGPTL8, regulate lipoprotein lipase (LPL) activity. Deficiency in either ANGPTL3 or ANGPTL8 reduces plasma triglyceride levels and increases LPL activity, whereas overexpression of either protein does the opposite. Recent studies suggest that ANGPTL8 may functionally interact with ANGPTL3 to alter clearance of plasma triglycerides; however, the nature of this interaction has remained elusive. We tested the hypothesis that ANGPTL8 forms a complex with ANGPTL3 and that this complex is necessary for the inhibition of vascular LPL by ANGPTL3. MethodsWe analyzed the interactions of ANGPTL3 and ANGPTL8 with each other and with LPL using co-immunoprecipitation, western blotting, lipase activity assays, and the NanoBiT split-luciferase system. We also used adenovirus injection to overexpress ANGPTL3 in mice that lacked ANGPTL8. ResultsWe found that ANGPTL3 or ANGPTL8 alone could only inhibit LPL at concentrations that far exceeded physiological levels, especially when LPL was bound to its endothelial cell receptor/transporter GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1). Physical interaction was observed between ANGPTL3 and ANGPTL8 when the proteins were co-expressed, and co-expression with ANGPTL3 greatly enhanced the secretion of ANGPTL8. Importantly, ANGPTL3–ANGPTL8 complexes had a dramatically increased ability to inhibit LPL compared to either protein alone. Adenovirus experiments showed that 2-fold overexpression of ANGPTL3 significantly increased plasma triglycerides only in the presence of ANGPTL8. Protein interaction assays showed that ANGPTL8 greatly increased the ability of ANGPTL3 to bind LPL. ConclusionsTogether, these data indicate that ANGPTL8 binds to ANGPTL3 and that this complex is necessary for ANGPTL3 to efficiently bind and inhibit LPL.

Angiopoietin-like 4 directs uptake of dietary fat away from adipose during fasting

ObjectiveAngiopoietin-like 4 (ANGPTL4) is a fasting-induced inhibitor of lipoprotein lipase (LPL) and a regulator of plasma triglyceride metabolism. Here, we examined the kinetics of Angptl4 induction and tested the hypothesis that ANGPTL4 functions physiologically to reduce triglyceride delivery to adipose tissue during nutrient deprivation. MethodsGene expression, LPL activity, and triglyceride uptake were examined in fasted and fed wild-type and Angptl4−/− mice. ResultsAngptl4 was strongly induced early in fasting, and this induction was suppressed in mice with access to food during the light cycle. Fasted Angptl4−/− mice manifested increased LPL activity and triglyceride uptake in adipose tissue compared to wild-type mice. ConclusionsAngptl4 is induced early in fasting to divert uptake of fatty acids and triglycerides away from adipose tissues.

Abstract 205: Inhibition of Angiopoietin-Like 3 Expression is a Potential Mechanism of Activation of Lipoprotein Lipase and of Lipid Lowering by Metformin

Dyslipidemias associated with primary lipid disorders or secondary to abnormal glucose metabolism are commonly seen metabolic disorders in the clinic. Of special interest is the diabetic dyslipidemia and its growing prevalence. Interestingly, metformin, a commonly used anti-diabetic drug also has potent lipid lowering activity. However, the mechanisms associated with this metformin activity are poorly understood. A key protein regulating the plasma lipid homeostasis is the enzyme lipoprotein lipase (LPL) which is found lining the capillary endothelium in tissue capillary beds. LPL hydrolyses the core triglycerides (TGs) of chylomicrons and very-low density lipoprotein (VLDL). Angiopoietin-like 3 (ANGPTL3), a secretory protein derived from liver, inhibits the lipolytic activity of LPL, resulting in an increase in plasma TGs. We investigated whether metformin regulates LPL and in effect plasma lipids, via regulation of ANGPTL3 in the liver. A single dose (150mg/kg) treatment of metformin for twenty-four hours in mice resulted in an increase in the LPL activity in plasma. Since metformin is frequently used in type 2 diabetes which is characterized by insulin resistance, a condition compounded by dietary fatty acids, we studied the relationship between metformin and ANGPTL3 in a human liver cell line treated with palmitic acid. Treatment with palmitic acid mimicked the conditions of insulin resistance in the liver and elevated the expression of ANGPTL3 in the liver which was inhibited by co-treatment with metformin. Gene and protein expression assays revealed a potent inhibition of ANGPTL3 expression and secretion from the hepatocytes upon treatment with metformin. We examined the role of sirtuin 1 (SIRT1)/adenosine monophosphate activated kinase (AMPK) in the metformin regulation of ANGPTL3 and observed that even though activation of SIRT1/AMPK axis inhibited the expression of ANGPTL3, metformin inhibition of ANGPTL3 was independent of SIRT1/AMPK as revealed by pharmacological inhibition and gene knockdown approaches. Our studies suggest that a potential mechanism of lipid lowering activity of metformin is the inhibition of expression of ANGPTL3, which results in an increase in LPL activity and a lowering of plasma lipids.

Long-term effects of angiotensin-(1–7) on lipid metabolism in the adipose tissue and liver

The angiotensin (Ang) converting enzyme 2/Ang-(1–7)/Mas axis has been described to have a beneficial role on metabolic disorders. In the present study, the use of a transgenic rat model that chronically overexpresses Ang-(1–7) enabled us to investigate the chronic effects of this peptide on lipid accumulation in the liver and adipose tissue. The transgenic group showed a marked tendency toward increased expression of peroxisome proliferator-activated receptor-γ (PPARγ) and decreased lipoprotein lipase (LPL) expression and activity in epididymal adipose tissue. We also showed that Mas receptor-knockout mice had decreased PPARγ expression in adipose tissue, accompanied by an increase in LPL activity. These results confirm the regulation of adipose tissue LPL activity by Ang-(1–7) and suggest that this occurs independent of PPARγ expression. The reduced adiposity index of transgenic rats, due to the effect of Ang-(1–7), was accompanied by a decrease in lipogenesis. These findings suggest a direct effect of Ang-(1–7) on lipogenesis, independent of the stimulatory effect of insulin. Furthermore, the decreased concentration of triacylglycerol in the liver of transgenic rats may result from increased activity of cytosolic lipases and decreased fatty acid uptake from the adipose tissue, determined from fatty acid-binding protein expression, and hepatic de novo fatty acid synthesis, evaluated by fatty acid synthase expression. The data clearly show that Ang-(1–7) regulates lipid metabolism in the adipose tissue and liver.

ANGPTL8 Promotes the Ability of ANGPTL3 to Inhibit Lipoprotein Lipase

Lipoprotein lipase (LPL) is critically important for the delivery of plasma lipoprotein–derived triglycerides to peripheral tissues. Activity of LPL is carefully regulated and misregulation of LPL can contribute to metabolic diseases including obesity, metabolic syndrome, and cardiovascular disease. Several members of the angiopoietin‐like (ANGPTL) family of proteins, including ANGPTL3 and ANGPTL8, regulate LPL activity. Deficiency in either ANGPTL3 or ANGPTL8 reduces plasma triglyceride levels and increases LPL activity, whereas overexpression of either protein does the opposite. Recent studies showed that ANGPTL8 overexpression only raises plasma triglycerides when ANGPTL3 is present suggesting that ANGPTL3 and ANGPTL8 work together to alter clearance of plasma triglycerides, however the nature of this interaction has remained elusive. We tested the hypothesis that ANGPTL8 forms a complex with ANGPTL3 and that this complex is necessary for efficient inhibition of LPL. We found that ANGPTL3 or ANGPTL8 alone could inhibit LPL only at concentrations that far exceeded physiological levels, especially when LPL was bound to its endothelial cell receptor/transporter GPIHBP1 (glycosylphosphatidylinositol‐anchored high‐density lipoprotein binding protein 1). Physical interaction was observed between ANGPTL3 and ANGPTL8 when the proteins were co‐expressed, and co‐expression with ANGPTL3 greatly enhanced the secretion of ANGPTL8. Importantly, the ability of ANGPTL3‐ANGPTL8 complexes to inhibit LPL was dramatically increased compared to either protein alone. Part of this improvement could be ascribed to an improved ability to bind LPL as protein interaction assays showed that ANGPTL8 increased the ability of ANGPTL3 to bind LPL. Together, these data suggest that ANGPTL8 binds to ANGPTL3, forming a complex that has an increased ability to bind and inhibit LPL.Support or Funding InformationThis work was supported by grants from the NHLBI (HL130146) and the Carver Medical Research Initiative

ANGPTL8 Blockade With a Monoclonal Antibody Promotes Triglyceride Clearance, Energy Expenditure, and Weight Loss in Mice

Angiopoietin-like protein (ANGPTL)8 is a negative regulator of lipoprotein lipase-mediated plasma triglyceride (TG) clearance. In this study, we describe a fully human monoclonal antibody (REGN3776) that binds monkey and human ANGPTL8 with high affinity. Inhibition of ANGPTL8 with REGN3776 in humanized ANGPTL8 mice decreased plasma TGs and increased lipoprotein lipase activity. Additionally, REGN3776 reduced body weight and fat content. The reduction in body weight was secondary to increased energy expenditure. Finally, single administration of REGN3776 normalized plasma TGs in dyslipidemic cynomolgus monkeys. In conclusion, we show that blockade of ANGPTL8 with monoclonal antibody strongly reduced plasma TGs in mice and monkeys. These data suggest that inhibition of ANGPTL8 may provide a new therapeutic avenue for the treatment of dyslipidemia with beneficial effects on body weight.

TNF-α decreases lipoprotein lipase activity in 3T3-L1 adipocytes by up-regulation of angiopoietin-like protein 4

Lipoprotein lipase (LPL) hydrolyzes lipids in plasma lipoproteins so that the fatty acids can be taken up and used by cells. The activity of LPL changes rapidly in response to changes in nutrition, physical activity and other conditions. Angiopoietin-like protein 4 (ANGPTL4) is an important controller of LPL activity. Both LPL and ANGPTL4 are produced and secreted by adipocytes. When the transcription blocker Actinomycin D was added to cultures of 3T3-L1 adipocytes, LPL activity in the medium increased several-fold. LPL mRNA decreased moderately during 5h, while ANGPTL4 mRNA and protein declined rapidly, explaining that LPL activity was increased. TNF-α is known to reduce LPL activity in adipose tissue. We have shown that TNF-α increased ANGPTL4 both at the mRNA and protein level. Expression of ANGPTL4 is known to be under control of Foxo1. Use of the Foxo1-specific inhibitor AS1842856, or knockdown of ANGPTL4 by RNAi, resulted in increased LPL activity in the medium. Both with ActD and with the Foxo1 inhibitor the cells became unresponsive to TNF-α. This study shows that TNF-α, by a Foxo1 dependent pathway, increases the transcription of ANGPTL4 which is secreted by the cells and causes inactivation of LPL.

Decreased eicosapentaenoic acid levels in acne vulgaris reveals the presence of a proinflammatory state

This study aimed to determine circulating levels of polyunsaturated fatty acids (PUFAs), secretory phospholipase A2 (sPLA2), lipoprotein lipase (LPL) and measure circulating protein levels of angiopoietin-like protein 3 (ANGPTL3), ANGPTL4, cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in patients with acne vulgaris. Serum from 21 control subjects and 31 acne vulgaris patients were evaluated for levels of arachidonic acid (AA, C20:4n- 6), dihomo-gamma-linolenic acid (DGLA, C20:3n-6), eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3). PUFA levels were determined by an optimized multiple reaction monitoring (MRM) method using ultra fast-liquid chromatography (UFLC) coupled with tandem mass spectrometry (MS/MS). Lipid profile, routine biochemical and hormone parameters were assayed by standard kit methods Serum EPA levels were significantly decreased while AA/EPA and DGLA/EPA ratio were significantly increased in acne vulgaris patients compared to controls. Serum levels of AA, DGLA and DHA showed no significant difference while activity of sPLA2 and LPL were significantly increased in acne vulgaris compared to controls. Results of this study reveal the presence of a proinflammatory state in acne vulgaris as shown by significantly decreased serum EPA levels and increased activity of sPLA2, AA/EPA and DGLA/EPA ratio. Increased LPL activity in the serum of acne vulgaris patients can be protective through its anti-dyslipidemic actions. This is the first study reporting altered EPA levels and increased sPLA2 activity in acne vulgaris and supports the use of omega-3 fatty acids as adjuvant treatment for acne patients.

Lipoprotein lipase does not increase significantly in the postprandial plasma

BackgroundPrevious reports have shown that lipoprotein lipase (LPL) activity significantly increases in the postprandial plasma associated with the increase of TG-rich lipoproteins. Therefore, we have reexamined those relationships using newly developed LPL assay with the different kinds of food intake. MethodsStandard meal (n=81), 50g of fat (n=54), 75g of glucose (n=25) and cookie (25g fat and 75g carbohydrate fat) (n=28) were administered in generally healthy volunteers. Plasma LPL, HTGL and TC, TG, LDL-C, HDL-C, RLP-C and RLP-TG were determined at subsequent withdrawal after the food intake. ResultsPlasma TG, RLP-C and RLP-TG were significantly increased at 8PM (2h after dinner of standard meal) compared with 8AM before breakfast within the same day. Also those parameters were significantly increased in 2–6h after fat load. However, the concentrations and activities of LPL and HTGL did not significantly increase in association with an increase in the TG and remnant lipoproteins. Also LPL concentration did not significantly increase after glucose and “cookie test” within 4h. ConclusionNo significant increase of LPL activity was found at CM and VLDL overload after different kinds of food intake when reexamined by newly developed assay for LPL activity and concentration.

Dietary n-3 LC-PUFAs affect lipoprotein lipase (LPL) and fatty acid synthase (FAS) activities and mRNA expression during vitellogenesis and ovarian fatty acid composition of female silver pomfret (Pampus argenteus) broodstock

We studied the effects of dietary n-3 LC-PUFAs on the activities and mRNA expression levels of tissue lipoprotein lipase (LPL) and fatty acid synthase (FAS) during vitellogenesis and ovarian fatty acid composition in female silver pomfret broodstock. Broodstock were fed one of four experimental diets for 185 days: FO (100% fish oil), FSO (70% fish oil + 30% soybean oil), SFO (30% fish oil + 70% soybean oil) or SO (100% soybean oil). The results revealed that hepatic LPL and FAS and ovarian FAS activities and mRNA expression levels significantly increased at vitellogenesis and postvitellogenesis relative to previtellogenesis, with no significant differences between these two stages, except for hepatic LPL mRNA expression. Dietary n-3 LC-PUFAs decreased tissue FAS and increased LPL activities and mRNA expression levels. The ovarian concentrations of 20:4n-6 (ARA), 20:5n-3 (EPA), 22:6n-3 (DHA) and n-3 LC-PUFAs were directly influenced by n-3 LC-PUFA levels. Total n-3 LC-PUFA concentrations in SO were 57% lower than those in FO, while 18:2n-6 concentrations in SO were 4.7 × higher than those in FO. These results revealed that high dietary n-3 LC-PUFAs levels significantly affected tissue lipid metabolism in female silver pomfret broodstock during vitellogenesis by upregulating LPL and downregulating FAS.

Mechanisms of triglyceride metabolism in patients with bile acid diarrhea.

Bile acids (BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor (FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes free fatty acids oxidation by inducing the expression of peroxisome proliferator-activated receptor α. FXR can reduce the expression of microsomal triglyceride transfer protein, which regulates the assembly of very low-density lipoproteins (VLDL). FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-II, very low-density lipoproteins receptor (VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-III, which increases lipoprotein lipase activity. There is currently minimal clinical data on triglyceride metabolism in patients with bile acid diarrhoea (BAD). Emerging data suggests that a third of patients with BAD have hypertriglyceridemia. Further research is required to establish the risk of hypertriglyceridaemia in patients with BAD and elicit the mechanisms behind this, allowing for targeted treatment.

Moderate alcohol consumption and triglyceridemia.

The review aims to summarize current knowledge on the effects of moderate alcohol consumption (1 standard drink a day for women; 2 drinks a day for men) on triglyceride concentration in circulation. Current evidence suggests that the relationship between alcohol consumption and triglyceridemia is J-shaped. Triglyceridemia is lowest in subjects who drink 10-20 g/alcohol a day. Such a J-shaped association is comparable with that described for the relationship between alcohol and cardiovascular risk. On the contrary, alcohol taken with a meal increases and prolongs postprandial triglyceridemia. Such effects of alcohol consumption may be at least partially explained by the effects of ethanol on lipoprotein lipase (LPL) activity. Long-term moderate alcohol consumption increases LPL activity, which may explain its TG-lowering effect. On the other hand, LPL activity is acutely downregulated by ethanol, which explains increased postprandial triglyceridemia.

Stimulation of Adipose Tissue Lipoprotein Lipase Activity Improves Glucose Metabolism and Increases High Density Lipoprotein Cholesterol in the Spontane

Insulin resistance syndrome (IRS), high blood pressure, elevated blood glucose and triacylglycerol-rich lipoproteins (TG-RL), as well as low levels of high-density lipoprotein (HDL-C) are disorders that combine to define metabolic syndrome (MetS). Metabolic syndrome is on the rise in the United States and is believed to be a powerful predictor of risk for diabetes and coronary events. Modulation of the activity of lipoprotein lipase (LPL) in MetS affects lipolysis of TG-RL, which has a direct correlation with the levels of plasma HDL-C. This study examined if increasing LPL activity by dietary means in a model for MetS leads to reduced IRS and increase in plasma HDL-C concentration. Ninety day-old Spontaneously Hypertensive Stroke-Prone male rats were originally fed lab chow diet for seven days. This was followed by feeding a fatty acid diet for 7 days containing one of the following: triolein (TO), trans fatty acids-rich (TFA, margarine) and 0 fatty acids (Control) with /without an LPL-rising drug (NO-1866) by gavages (5 mg or 25 mg/kg b. wt.). The results show that blood glucose and triacylglycerol levels were decreased with NO-1886. HDL-C levels increased with NO-1866 in the control and triolein group but not in the TFA group. Animals in the triolein group had higher levels of phospholipids and lower levels of insulin. Inclusion of NO-1866 lowered HOMA-IR by almost 40% in the control and the TFA group, but no further reduction was observed in the TO group. The control TFA groups had up to 45% higher HOMA-IR than the TO group. Overall the data suggest that raising the activity of lipoprotein lipase by dietary means, including the feeding of monounsaturated fat may increase HDL-C, reduce plasma triacylglycerol and other indices of MetS risk, and thus may decrease the incidence of vascular complications through the normalization of lipid metabolism in subjects with MetS.

ANGPTL4 mediates shuttling of lipid fuel to brown adipose tissue during sustained cold exposure.

Brown adipose tissue (BAT) activation via cold exposure is increasingly scrutinized as a potential approach to ameliorate cardio-metabolic risk. Transition to cold temperatures requires changes in the partitioning of energy substrates, re-routing fatty acids to BAT to fuel non-shivering thermogenesis. However, the mechanisms behind the redistribution of energy substrates to BAT remain largely unknown. Angiopoietin-like 4 (ANGPTL4), a protein that inhibits lipoprotein lipase (LPL) activity, is highly expressed in BAT. Here, we demonstrate that ANGPTL4 is part of a shuttling mechanism that directs fatty acids derived from circulating triglyceride-rich lipoproteins to BAT during cold. Specifically, we show that cold markedly down-regulates ANGPTL4 in BAT, likely via activation of AMPK, enhancing LPL activity and uptake of plasma triglyceride-derived fatty acids. In contrast, cold up-regulates ANGPTL4 in WAT, abolishing a cold-induced increase in LPL activity. Together, our data indicate that ANGPTL4 is an important regulator of plasma lipid partitioning during sustained cold.

Mangiferin supplementation improves serum lipid profiles in overweight patients with hyperlipidemia: a double-blind randomized controlled trial

Our previous studies have shown that mangiferin decreased serum triglycerides and free fatty acids (FFAs) by increasing FFAs oxidation in both animal and cell experiments. This study sought to evaluate the effects of mangiferin on serum lipid profiles in overweight patients with hyperlipidemia. Overweight patients with hyperlipidemia (serum triglyceride ≥ 1.70 mmol/L, and total cholesterol ≥ 5.2 mmol/L) were included in this double-blind randomized controlled trial. Participants were randomly allocated to groups, either receiving mangiferin (150 mg/day) or identical placebo for 12 weeks. The lipid profile and serum levels of mangiferin, glucose, L-carnitine, β-hydroxybutyrate, and acetoacetate were determined at baseline and 12 weeks. A total of 97 participants completed the trial. Compared with the placebo control, mangiferin supplementation significantly decreased the serum levels of triglycerides and FFAs, and insulin resistance index. Mangiferin supplementation also significantly increased the serum levels of mangiferin, high-density lipoprotein cholesterol, L-carnitine, β-hydroxybutyrate, and acetoacetate, and increased lipoprotein lipase activity. However, there were no differences in the serum levels of total cholesterol, low-density lipoprotein cholesterol, serum glucose, and insulin between groups. Mangiferin supplementation could improve serum lipid profiles by reducing serum triglycerides and FFAs in overweight patients with hyperlipidemia, partly due to the promotion of FFAs oxidation.