Hepatic Triglyceride Lipase Activity Research Articles

FRI089 Massive Hypertriglyceridemia? Think Oral Contraceptive Pills!

Abstract Disclosure: I. Ali: None. M. Hamdi: None. Introduction: Oral contraceptive pills (OCPs) are common cause of Hypertriglyceridemia (TG) that should be recognized early by clinicians. Concern is raised regarding pursing further genetic test for Familial hypertriglyceridemia for female who developed massive hyper triglyceridemic after starting hormonal therapy. Case: A 37-year-old female patient with history of prediabetes with A1c of 5.7% and one attack of pancreatitis. Normal BMI, No regular medications, negative family history for lipid disorder. Rare social intake of alcohol. Routine annual lab showed triglycerides level of 164 in 2016, otherwise normal biochemical evaluation. No treatment pursued. Later She was started on OCPs (Kariva 0.15-0.02 mg) for contraception. Late 2019, blood work-up showed cholesterol level of 979, TG of 3170 and HDL level of 22. She was started on a statin therapy and fenofibrates beside stopping OCP, she maintained normal lipid profile while being off OCPs, until 2022 when she restarted an OCPs (Lo Loestrin 1mg-10 mcg) for 2 months that resulted in elevated cholesterol level of 1222, triglycerides of 5177 and HDL of 10.OCP was stopped, lipids level trended down with cholesterol of 961, triglycerides of 2005 and HDL of 22 then normalized after 2 months. Patient did not have any clinical symptom or complain. Discussion: High triglyceride concentration is an independent predictor of coronary heart disease and ischemic stroke. Many patients with triglycerides >1000 mg/dl have familial hypertriglyceridemia with superimposed additional exogenous factors which further raise triglyceride concentrations like exogenous estrogens, SERMs, hyperestrogenemia of pregnancy, poorly controlled diabetes mellitus, hypothyroidism, alcohol excess, exogenous corticosteroids, and drugs including isotretinoin and protease inhibitors. OCP induced hypertriglyceridemia occurs due to estrogen’s action in decreasing hepatic triglyceride lipase and lipoprotein lipase activity. This causes an overall increase in low and intermediate-density triglycerides and cholesterol that can increase free fatty acids to toxic level. The marked increase of TG and cholesterol in this patient while being on OCP is unusual and strongly indicate underlying familial hypertriglyceridemia exacerbated by starting OCP. Further genetic work up is being done. As OCP or other estrogen therapy are frequently given unwittingly to women with preexisting hypertriglyceridemia that lead to severe clinical consequences. Estrogen containing medication should not be considered if fasting triglyceride is above 500 mg/dl. In women on hormonal treatment with treatment-resistant hypertriglyceridemia, the likelihood that the hormonal treatment is nullifying drug efficacy is high so it should be stopped for a short trial while continuing modifying triglyceride-lowering medications. Presentation: Friday, June 16, 2023

Farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5) signaling pathways improved the hepatic lipid metabolism in hybrid grouper

In the present study, juvenile hybrid grouper (Epinephelus fuscoguttatus♀ × E. lanceolatus♂) were intraperitoneally injected with taurocholic acid (I-TCA), obeticholic acid (FXR agonist, I-T747), guggulsterone (FXR antagonist, I-TGU), SBI-115 (TGR5 antagonist, I-TSBI), and INT-777 (TGR5 agonist, I-T777), respectively. The results showed that the fish injected with 50 mg kg−1 TCA three times during a 144 h period exhibited significantly lower hepatic lipid accumulation, compared to other concentrations and periods. Compared to the I-TCA group, the I-T747 treatment significantly increased the activities of hepatic adipose triglyceride lipase (ATGL) and carnitine palmitoyltransferase 1 (CPT1), as well as the expression of lipolysis and fatty acid uptake genes, while significantly decreased the conten of hepatic crude lipid, the activity of CPT1, and the expression of lipogenesis genes. Meanwhile, the I-TGU treatment significantly increased hepatic lipid deposition and the expression of lipogenesis genes. Compared to the I-TCA group, the I-T777 treatment did not significantly affect the parameters related to lipid deposition, but it significantly decreased the activities of acetyl-CoA carboxylase (ACC), CPT1, and fatty acid synthase (FAS), while significantly increasing the activity of ATGL and the expression of lipolysis and fatty acid uptake-related genes. Meanwhile, the I-TSBI treatment significantly increased the hepatic lipid accumulation, the activities of ACC, CPT1 and FAS, and the expression of lipogenesis and lipogenic transcriptional factors genes. In conclusion, activation of the FXR protected against the hepatic lipid accumulation by enhancing the lipolysis, while inhibition of FXR or TGR5 induced the hepatic lipid accumulation by enhancing the lipogenesis in hybrid grouper.

Need for Screening Triglyceride Levels in Women on Oral Contraceptives

Introduction: Oral contraceptive pills (OCPs) are the most used form of reversible contraceptives by women. Major risks are cardiovascular but OCPs also cause secondary hypertriglyceridemia (HTG) through effects of estrogen, which decreases hepatic triglyceride lipase and lipoprotein lipase activity. This causes increased triglycerides, cholesterol and free fatty acids,1 which then in turn can lead to life-threatening acute pancreatitis. Case Description: A 23-year-old morbidly obese (BMI 38.2 mg/kg2) female presented with severe epigastric pain, nausea and vomiting. She had a history of mild intermittent asthma, recently diagnosed pre-diabetes and recently started on OCPs. Initial labs were consistent with diabetic ketoacidosis with glucose 528 mg/dL (65-115 mg/dL), anion gap 21 mEq/L (5-15 mEq), and beta-hydroxybutyrate 2.00 mmol/L (0.02-0.27 mmol/L); and acute pancreatitis with triglyceride 4,425 mg/dL (30-200 mg/dL) and lipase >600 U/L (8-78 UL), confirmed on imaging.She rapidly deteriorated, developing acute hypoxemic respiratory distress requiring intubation and distributive shock requiring three vasopressors. She progressed into multi-organ failure with acute respiratory distress syndrome, ischemic liver and acute renal failure despite insulin drip, colloidal fluid resuscitation, continuous veno-venous hemofiltration and high positive end-exploratory pressures. She developed rhabdomyolysis, followed by abdominal compartment syndrome requiring decompressive laparotomy that resulted in large volume blood loss and retroperitoneal necrosis needing multiple laparotomies. Ultimately, she became non-responsive off sedation, attributed to malignant cerebral edema that progressed to brain herniation.While HTG was likely the cause of her pancreatitis, she had normal triglyceride levels on prior routine lab work while not on OCPs. Discussion: Severe acute pancreatitis is a life-threatening complication of HTG which may be precipitated by use of OCPs. We believe that there is a need for more research in this field and even propose periodic monitoring of HTG in women taking OCPs given the severity of the consequences. While there are currently no guidelines for monitoring lipid levels in women on OCP, appropriate clinical awareness of physicians prescribing OCPs to patients may prevent fatal outcomes.

Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis.

While it is well-established that alterations in the portal vein insulin/glucagon ratio play a major role in causing dysregulated hepatic glucose metabolism in type 2 diabetes (T2D)1–3, the mechanisms by which glucagon alters hepatic glucose production and mitochondrial oxidation remain poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing hepatic adipose triglyceride lipase activity, intrahepatic lipolysis, hepatic acetyl-CoA content, and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation, mediated by stimulation of the inositol triphosphate receptor-1 (InsP3R-I). Chronic physiological increases in plasma glucagon concentrations increased mitochondrial hepatic fat oxidation and reversed diet-induced hepatic steatosis and insulin resistance in rats and mice; however, the effect of chronic glucagon treatment to reverse hepatic steatosis and glucose intolerance was abrogated in InsP3R-I knockout mice. These results provide new insights into glucagon biology and suggest that InsP3R-I may be a novel therapeutic target to reverse nonalcoholic fatty liver disease and T2D.

An automated method for measuring lipoprotein lipase and hepatic triglyceride lipase activities in post-heparin plasma

BackgroundLipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) play a central role in triglyceride-rich lipoprotein metabolism by catalyzing the hydrolysis of triglycerides. Quantification of LPL and HTGL activity is useful for diagnosing lipid disorders, but there has been no automated method for measuring these lipase activities. MethodsThe automated kinetic colorimetric method was used for assaying LPL and HTGL activity in the post-heparin plasma using the natural long-chain fatty acid 2-diglyceride as a substrate. LPL activity was determined with apoCII and HTGL activity was determined without apoCII with 2 channel of auto-analyzer. ResultsThe calibration curve for dilution tests of the LPL and HTGL activity assay ranged from 0.0 to 500 U/L. Within-run CV was obtained within a range of 5%. No interference was observed in the testing of specimens containing potentially interfering substances. The measurement range of LPL activity in the post-heparin plasma was 30–153 U/L, while HTGL activity was 135–431 U/L in normal controls. ConclusionsThe L PL and HTGL activity assays are applicable to quantitating the LPL and HTGL activity in the post-heparin plasma. This assay is more convenient and faster than radiochemical assay and highly suitable for the detection of lipid disorders.

Total Cholesterol as an Indicator for Severity of Liver Disease

Introduction: Alcohol and hepatitis-C induced cirrhosis continue to be a highly prevalent problem in our patient population. A retrospective study was subsequently conducted to determine the correlation between the severity of liver disease and total cholesterol in patients with alcohol and/or hepatitis-C induced cirrhosis. Methods: In total, 237 patients above the age of 18 with a diagnosis of cirrhosis secondary to hepatitis C and/or alcohol use were included in the study. The included patients were either admitted to the hospital or seen in the clinic between January 2012 and December 2014. Patients actively taking statins, diagnosed with cholestasis or primary biliary cirrhosis were excluded from the study. Results: Linear regression analysis was performed to elucidate the correlation between total serum cholesterol and each of the validated liver disease severity scores (MELD and MELD-Na scores). There was a statistically significant inverse correlation (P < 0.0001) between serum total cholesterol and both these scores (Figures 1 and 2). Notably, this study also demonstrated a direct correlation between serum sodium levels and serum total cholesterol levels (P= 0.0020) (Figure 3).Figure 1Figure 2Figure 3Conclusion: Severe intrinsic hepatic dysfunction leads to decreased total cholesterol levels. The mechanisms of dysfunctional lipid metabolism in cirrhosis is not yet fully understood, however it has been shown that lipoproteins and plasma lipids tend to decrease with hepatocellular injury. It is thought that fundamental metabolic defects are related to the alteration in activity of enzymes involved in lipid metabolism including lecithin-cholesterol acyltransferase (LCAT) and apoprotein activator deficiencies. Impaired hepatic triglyceride lipase (H-TGL) and lipoprotein lipase (LPL) activity; defective remnant lipoprotein clearance by the liver have also been implicated. It is likely that the mechanisms for deranged lipid metabolism in cirrhosis from alcoholic, non-alcoholic and viral causes involve a complex interplay between enzyme dysregulation, disease-specific hepatic dysfunction, and host-specific factors. The direct correlation between serum sodium levels and serum total cholesterol levels alludes to the pathophysiology of advanced intrinsic hepatic dysfunction where there is splanchnic vasodilatation with arterial hypotension, decreased intravascular volume with impairment of renal function and subsequent water and sodium retention leading to dilutional hyponatremia.

Understanding of Diabetic Dyslipidemia by Using the Anion-Exchange High Performance Liquid Chromatography Data.

Type 2 diabetes and dyslipidemia are cardiovascular risk factors which should be managed [1]. However, the precise lipoprotein profiles and the underlying mechanisms for diabetic dyslipidemia remain largely unknown. We previously developed an anion-exchange liquid chromatographic method (AEX-HPLC) which can measure cholesterol levels of triglyceride (TG)-rich lipoproteins such as very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and chylomicron (CM) in addition to low-density lipoprotein (LDL) and high-density lipoprotein (HDL) [2]. Here we compared lipoprotein profiles obtained by our previous studies using AEX-HPLC in young lean men [3], subjects with low Framingham risk score (FRS) [4, 5], type 2 diabetic patients without obesity and type 2 diabetic patients with obesity [6, 7]. The mean ± SD values of age, body mass index, HbA1c in in young lean men (n = 7) [3], low FRS subjects (n = 304) [4], type 2 diabetic patients without obesity (n = 194) [6], and type 2 diabetic patients with obesity (n = 5) [7] were 24 ± 2, 51 ± 8, 63 ± 13, and 60 ± 9 years old, 20.8 ± 2.2, 23.8 ± 3.0, 23.1 ± 2.0, and 29.5 ± 7.0 kg/m2, 5.0 ± 0.2, 5.4 ± 0.5, 6.3 ± 1.0, and 9.1±2.1%, respectively. HDL-cholesterol (HDL-C) in type 2 diabetes (49.9 ± 16.6 mg/dL (1.29 ± 0.43 mmol/L)), especially in type 2 diabetic patients with obesity (36.4 ± 5.3 mg/dL (0.94 ± 0.14 mmol/L)) was lower than young lean men (59.4 ± 10.1 mg/dL (1.54 ± 0.26 mmol/L)) and low FRS subjects (57.6 ± 14.7 mg/dL (1.49 ± 0.38 mmol/L)). IDL-C in type 2 diabetes was higher than other two groups, and IDL-C was higher in the order of type 2 diabetic patients with obesity (9.8 ± 3.0 mg/dL (0.25 ± 0.08 mmol/L)), type 2 diabetic patients without obesity (9.3 ± 4.6 mg/dL (0.24 ± 0.12 mmol/L)), low FRS subjects (7.3 ± 3.1 mg/ dL (0.19 ± 0.08 mmol/L)), young lean men (4.3 ± 2.2 mg/dL (0.11 ± 0.06 mmol/L)). VLDL-C clearly showed higher values in the order of type 2 diabetic patients with obesity (27.3 ± 22.7 mg/dL (0.71 ± 0.59 mmol/L)), type 2 diabetic patients without obesity (20.1 ± 16.2 mg/dL (0.52 ± 0.42 mmol/L)), low FRS subjects (16.6 ± 12.8 mg/dL (0.43 ± 0.33 mmol/L)), and young lean men (4.0 ± 4.6 mg/dL (0.10 ± 0.12 mmol/L)). LDL-C and CM-C did not show the characteristic profile for diabetes. According to accumulation of our previous AEX-HPLC data [3, 4, 6, 7], the characteristics in diabetic dyslipidemia is reduced HDL-C, and increased IDL-C and VLDL-C, which is further deteriorated by complication with obesity. Relative insulin deficiency due to insulin resistance increases activity and expression of hormone-sensitive lipase (HSL) in adipose tissue, which catalyzes the breakdown of TG, releasing free fatty acids (FFA) (Fig. 1) [8]. Insulin promotes apoB100 degradation, and hepatic insulin resistance causes reduction of apoB100 degradation [9]. Insulin resistance also induces an enhanced expression of microsomal TG transfer protein (MTP), a key enzyme involved in VLDL assembly [10]. In type 2 diabetes, increased FFA entry to liver, reduced degradation of apoB100 and enhanced expression of MTP may elevate hepatic production of VLDL. Relative insulin deficiency also decreases the activity of lipoprotein lipase (LPL), the rate-limiting enzyme of the catabolism of TG-rich lipoproteins such as CM, VLDL and IDL [11]. The formation of HDL is related with the catabolism of TG-rich lipoproteins by LPL [12]. Therefore, reduced LPL activity increases IDL and VLDL, and reduces HDL. The activity of hepatic TG lipase (HTGL), the enzyme that facilitates the catabolism of HDL, is correlated with insulin requirement [13]. In type 2 diabetes, low serum HDL-C may be partially due to an increased rate of clearance by HTGL [13]. LDL size and buoyancy are inversely proportional to HTGL activity [14], and patients with high HTGL have smaller, denser LDL particles, as compared with subjects with low HTGL activity [15]. Increased HTGL activity due Manuscript accepted for publication March 03, 2016

Conjugated linoleic acid alters growth performance, tissue lipid deposition, and fatty acid composition of darkbarbel catfish (Pelteobagrus vachelli).

Fatty liver syndrome is a prevalent problem of farmed fish. Conjugated linoleic acid (CLA) has received increased attention recently as a fat-reducing fatty acid to control fat deposition in mammals. Therefore, the aim of the present study was to determine whether dietary CLA can reduce tissue lipid content of darkbarbel catfish (Pelteobagrus vachelli) and whether decreased lipid content is partially due to alterations in lipid metabolism enzyme activities and fatty acid profiles. A 76-day feeding trial was conducted to investigate the effect of dietary CLA on the growth, tissue lipid deposition, and fatty acid composition of darkbarbel catfish. Five diets containing 0 % (control), 0.5 % (CLA0.5), 1 % (CLA1), 2 % (CLA2), and 3 % (CLA3) CLA levels were evaluated. Results showed that fish fed with 2-3 % CLA diets showed a significantly lower specific growth rate and feed conversion efficiency than those fed with the control diet. Dietary CLA decreased the lipid contents in the liver and intraperitoneal fat with the CLA levels from 1 to 3 %. Fish fed with 2-3 % CLA diets showed significantly higher lipoprotein lipase and hepatic triacylglycerol lipase activities in liver than those of fish fed with the control, and fish fed with 1-3 % CLA diets had significantly higher pancreatic triacylglycerol lipase activities in liver than those of fish fed with the control. Dietary CLA was incorporated into liver, intraperitoneal fat, and muscle lipids, with higher percentages observed in liver compared with other tissues. Liver CLA deposition was at the expense of monounsaturated fatty acids (MUFA). In contrast, CLA deposition appeared to be primarily at the expense of MUFA and n-3 polyunsaturated fatty acids (PUFA) in the intraperitoneal fat, whereas in muscle it was at the expense of n-3 PUFA. Our results suggested that CLA at a 1 % dose can reduce liver lipid content without eliciting any negative effect on growth rate in darkbarbel catfish. This lipid-lowering effect could be in part due to an increment in the activity of lipid metabolism enzymes and an extensive interconversion of fatty acids. Although CLA deposition in muscle (0.66-3.19 % of total fatty acids) are higher than presented in natural sources of CLA, EPA (C20:5n-3) in fish muscle appears simultaneously expendable, when the fish fed with 2-3 % CLA.

Immunosuppression in Renal Transplantation and Dyslipidemia, Which Factors Should Be Considered?

Dear Editor, Secondary dyslipidemia is the most common form of lipid metabolism derangement, due to the fact that primitive dyslipidemia represent only 0.5-2% of cases (1). Transplantation is a common cause of dyslipidemia, it has been shown that it defines metabolic syndrome, a common finding in renal transplant recipients (RTR) (2), and statins are within the top 15 drugs used by these patients (3). Moreover the increasing prescription of statins in this population is related to the frequent screening for dyslipidemia in transplanted patients (3). Immunosuppression could cause hypercholesterolemia and Cyclosporine (CsA) is widely used as immunosuppressive drug even if in the recent years physicians prescribe more frequently Tacrolimus than CsA (3). Moreover renal function in RTR is reduced and in many causes they are long-term treated with steroids. An additional risk factor for dyslipidemia should be taken into account in RTR such as chronic kidney disease, a condition in which triglycerides are increased and HDL-cholesterol is reduced. The main causes of these alterations are increased plasma levels of VLDL, IDL, LDL, Lp(a) and reduced activity of hepatic triglyceride lipase and peripheral lipoprotein lipase (4). Hypercholesterolemia secondary to steroids is due to hyperinsulinemia and peripheral insulin resistance increases hepatic synthesis of VLDL, moreover steroids reduce the release of ACTH with up-regulation of LDL-cholesterol hepatic receptors (5). On the contrary, the mechanism responsible for hypercholesterolemia during CsA treatment is still a matter of debate. CsA is a lipophilic drug and is carried by HDL and LDL cholesterol; it has been suggested that the drug impairs hepatic clearance of LDL (6). Moreover hepatic sterol regulatory element binding protein-2 is activated leading to increased VLDL synthesis, and secretion of bile and bile salts is impaired causing reduced cholesterol elimination (7). Hosseini et al. (8) study evaluated the relationship between CsA and dyslipidemia in RTR; they showed that plasma levels of cholesterol and triglycerides started increasing 4-12 months after beginning of immunosuppressive therapy, while subsequently HDL-cholesterol decreased and LDL-cholesterol increased. Logistic regression analysis showed that female gender and serum creatinine were the major risk factors for hypercholesterolemia and hypertriglyceridemia; on the contrary, CsA was not related to them. Similar results were shown by Laufer et al. (9) in heart transplant recipients. In their study the main risk factors were the history of cardiac disease leading to transplantation and steroids therapy. Hricik et al. (10) evaluated RTR and showed that reduction of steroid’s dose caused decreasing total plasma cholesterol levels. Cardiovascular disease is a major problem in RTR due to its relationship with morbidity and mortality and graft loss. Statins seem to have a protective effect in RTR, especially on risk of major cardiac events and they need to be considered during patients follow-up (4).

Upregulation of fatty acid synthesis and the suppression of hepatic triglyceride lipase as a direct cause of hereditary postprandial hypertriglyceridemia in rabbits

Rabbits with hereditary postprandial hypertriglyceridemia exhibit central obesity and are regarded as a reliable model for metabolic syndrome. This study was performed to gain insight into the affected process of lipid metabolism and into the causative genes of the postprandial hypertriglyceridemia rabbits. Eleven genes that play key roles in lipid metabolism were selected, their mRNA levels were assessed by quantitative PCR, and their expressions were compared among postprandial hypertriglyceridemia rabbits using Japanese white rabbits as the control. Two genes appeared to be in causal connection with postprandial hypertriglyceridemia, and these were regarded as likely candidates for the pathogenesis. One was the fatty acid synthase gene, which had an expression constitutively higher in postprandial hypertriglyceridemia rabbits than in Japanese white rabbits during the fasting state and reached quite high levels after feeding. The other was the gene for hepatic triglyceride lipase with an expression that was approximately one order lower than that found in the Japanese white rabbits. The low plasma hepatic triglyceride lipase activities were consistent with the low levels of the transcript in the livers of the postprandial hypertriglyceridemia rabbits. Thus, elevated fatty acid synthesis and defected lipid hydrolysis together would cause the postprandial hypertriglyceridemia in postprandial hypertriglyceridemia rabbits.

Hypotriglyceridemic effects of apple polyphenols extract via up-regulation of lipoprotein lipase in triton WR-1339-induced mice

To investigate the anti-hyperlipidemic effects of apple polyphenols extract (APE) in Triton WR-1339-induced endogenous hyperlipidemic model. Firstly, APE was isolated and purified from the pomace of Red Fuji Apple and contents of individual polyphenols in APE were determined using high-performance liquid chromatography-mass spectrometry (HPLC-MS). Secondly, forty male National Institude of Health (NIH) mice were randomly divided into 5 groups with 8 animals in each group. The Fenofibrate Capsules (FC) group and APE groups received oral administration of respective drugs for 7 consecutive days. All mice except those in the normal group were intravenously injected through tail vein with Triton WR-1339 on the 6th day. Serum and livers from all the mice were obtained 18 h after the injection. The changes in serum total cholesterol (TC), triglyceride (TG), lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) were measured by respective kits. Finally, expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) mRNA was measured by real-time reverse transcription-polymerase chain reaction (RT-PCR) method. RESULTS SERUM TC AND TG LEVELS SIGNIFICANTLY INCREASED IN TRITON WR-1339-INDUCED MODEL GROUP COMPARED WITH THE NORMAL GROUP (P<0.01). ORAL ADMINISTRATION OF APE [200 AND 400 MG/(KG DAY)] DOSE-DEPENDENTLY REDUCED THE SERUM LEVEL OF TG IN HYPERLIPIDEMIC MICE (P<0.01). SERUM LPL AND HTGL ACTIVITIES SIGNIFICANTLY DECREASED IN TRITON WR-1339-INDUCED MODEL GROUP COMPARED WITH THE NORMAL GROUP (P<0.05). ORAL ADMINISTRATION OF APE [200 AND 400 MG/(KG DAY)] DOSE-DEPENDENTLY ELEVATED THE SERUM ACTIVITY OF LPL IN HYPERLIPIDEMIC MICE (P<0.05 OR P<0.01). FURTHERMORE, COMPARED WITH THE NORMAL GROUP, HEPATIC MRNA LEVEL OF PPARα IN THE MODEL GROUP SIGNIFICANTLY DECREASED (P<0.01). ORAL ADMINISTRATION OF APE [200 AND 400 MG/(KG DAY)] DOSE-DEPENDENTLY ELEVATED THE EXPRESSION OF PPARα IN HYPERLIPIDEMIC MICE (P<0.05 OR P<0.01): APE could reduce TG level via up-regulation of LPL activity, which provides new evidence to elucidate the anti-hyperlipidemic effects of APE.

Effects of anabolic androgenic steroids on chylomicron metabolism

ObjectiveTo evaluate the effects of anabolic androgenic steroids (AAS) on chylomicron metabolism. MethodsAn artificial lipid emulsion labeled with radioactive cholesteryl ester (CE) and triglycerides (TG) mimicking chylomicrons was intravenously injected into individuals who regularly weight trained and made regular use of AAS (WT+AAS group), normolipidemic sedentary individuals (SDT group) and individuals who also regularly weight trained but did not use AAS (WT group). Fractional clearance rates (FCR) were determined by compartmental analysis for emulsion plasma decay curves. ResultsFCR-CE for the WT+AAS group was reduced (0.0073±0.0079min−1, 0.0155±0.0100min−1, 0.0149±0.0160min−1, respectively; p<0.05), FCR-TG was similar for both the WT and SDT groups. HDL-C plasma concentrations were lower in the WT+AAS group when compared to the WT and SDT groups (22±13; 41±7; 38±13mg/dL, respectively; p<0.001). Hepatic triglyceride lipase activity was greater in the WT+AAS group when compared to the WT and SDT groups (7243±1822; 3898±1232; 2058±749, respectively; p<0.001). However, no difference was observed for lipoprotein lipase activity. ConclusionsData strongly suggest that AAS may reduce the removal from the plasma of chylomicron remnants, which are known atherogenic factors.

Postprandial triglyceridemia after single dose of alcohol in healthy young men

Background and AimsModerate alcohol consumption provides protection against cardiovascular disease primarily due to increase of HDL-cholesterol. However, it also has some adverse effects on metabolism of triglycerides (TG). Therefore, we addressed the question how a single dose of alcohol affects postprandial lipemia and activities of two enzymes playing a critical role in regulation of triglyceridemia, lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL). Methods and ResultsEight healthy volunteers were given a single dose of alcohol (vodka; 0.6 g of ethanol/kg of body weight) together with a fat load (0.7 g of fat/kg of body weight) in an experimental breakfast or together with dinner 12 h before the experimental breakfast. In comparison to control experiment, alcohol given with breakfast induced increased and prolonged postprandial response of triglyceride-rich lipoproteins (TRL; d < 1.006 g/ml). At the same time TG accumulated also in intermediate density lipoproteins (IDL; d 1.006–1.019 g/ml). Alcohol given in the evening before the experiment increased fasting TG concentration but did not affect changes in TRL and IDL concentrations. LPL activity measured both in vivo using intravenous fat tolerance test and in vitro and HTGL activity were determined at the end of experiments (after 7.5 h of postprandial lipemia study). Neither was affected by a single dose of alcohol. ConclusionsSingle dose of alcohol induces immediate and profound changes in metabolism of TRL and IDL. The same dose of alcohol given 12 h before meal does affect baseline TG concentration but not the postprandial changes of triglyceridemia.

Activation of lipoprotein lipase increases serum high density lipoprotein 2 cholesterol and enlarges high density lipoprotein 2 particles in rats

It is known that postheparin plasma lipoprotein lipase (LPL) activity correlates with serum high density lipoprotein cholesterol (HDL-C) levels in humans and animals. Furthermore, LPL has been reported to cause enlargement of HDL particle size in vitro. However, these effects have not yet been experimentally proven. The aim of this study was to determine whether LPL has a role in increase in HDL-C and enlargement of HDL particle by activating the LPL function with NO-1886, the LPL promoting agent. NO-1886 administration increased postheparin plasma LPL activity without influencing hepatic triglyceride lipase activity. NO-1886 increased serum HDL2-cholesterol (HDL2-C) concentration and enlarged HDL2 particle size, but did not increase serum HDL3-cholesterol concentration or enlarge HDL3 particle size. Also, serum HDL2-C concentrations were positively correlated with HDL2 particle size (r=0.910). Our study demonstrates that the LPL activation induced with NO-1886 may cause production of HDL2-C by catabolism of triglyceride-rich lipoproteins and enlarges HDL2 particle size in rats.

透析患者の血清VLDL-IDL異常とPHLA(LPLおよびH-TGL活性)変動

透析患者の血清VLDL-IDL異常とPHLA(LPLおよびH-TGL活性)変動

Effects of a Purified Saponin Mixture from Alfalfa on Plasma Lipid Metabolism in Hyperlipidemic Mice

Alfalfa (Medicago sativa L.) is a genus distributed widely throughout the world and considered as the richest land source of nature products. In this study, we obtained a purified saponin mixture (PSM) through a simple, repeatable and controllable separation method from alfalfa. The compounds of the saponin mixture were identified as Azukisaponin V and Soyasaponin I, which was determined as 79.26 and 20.74% respectively by HPLC-evaporative light scattering detection (ELSD) method. The effects of PSM on plasma lipid metabolism were studied in hyperlipidemic mice induced by Triton WR-1339. Results showed that PSM could significantly inhibit the increase of total cholesterol (TC), triacylglycerol (TG) and low density lipoprotein cholesterol (LDL-C) levels, and the decrease of plasma high density lipoprotein cholesterol (HDL-C) level in plasma of hyperlipidemic mice induced by Triton WR-1339. Further study demonstrated that PSM not only enhanced the activities of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) in liver, but also increased their mRNA levels in hyperlipidemic mice. The results above indicate that PSM from alfalfa exerts effects on plasma lipid metabolism through elevating the activity of liver lipases in hyperlipidemic mice. The obtained data would be a good contribution to the development and utilization of alfalfa in the world.

Association of angiopoietin-like protein 3 with hepatic triglyceride lipase and lipoprotein lipase activities in human plasma

The relationship between plasma angiopoietin-like protein 3 (ANGPTL3), and lipoprotein lipase (LPL) activity and hepatic triglyceride lipase (HTGL) activity has not been investigated in the metabolism of remnant lipoproteins (RLPs) and high-density lipoprotein (HDL) in human plasma. ANGPTL3, LPL activity, HTGL activity, RLP-C and RLP-TG and small, dense LDL-cholesterol (sd LDL-C) were measured in 20 overweight and obese subjects in the fasting and postprandial states. Plasma TG, RLP-C, RLP-TG and sd LDL-C were inversely correlated with LPL activity both in the fasting and postprandial states, but not correlated with HTGL activity and ANGPTL3. However, plasma HDL-C was positively correlated with LPL activity both in the fasting and postprandial states, while inversely correlated with HTGL activity. ANGPTL3 was inversely correlated with HTGL activity both in the fasting and postprandial states, but not correlated with LPL activity. HTGL plays a major role in HDL metabolism, but not RLP metabolism. These findings suggest that ANGPTL3 is strongly associated with the inhibition of HTGL activity and regulates HDL metabolism, but not associated with the inhibition of LPL activity for the metabolism of RLPs in human plasma.

A Case of Adolescent Hyperlipoproteinemia with Xanthoma and Acute Pancreatitis, Associated with Decreased Activities of Lipoprotein Lipase and Hepatic Triglyceride Lipase

Lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) enhance the hydrolysis of triglycerides (TG) transported by chylomicron (CM) and very-low-density lipoprotein (VLDL). We report a case of severe hyperchylomicronemia with high levels of remnant lipoprotein and total cholesterol (T-Chol) in a 15-year-old boy. Precise examination of the lipid profile showed decreased activities of both LPL and HTGL, although the protein mass for LPL and HTGL were maintained. In addition, bezafibrate treatment effectively ameliorated hypertriglyceridemia in this case. This is the first case of hyperchylomicronemia with decreased activities and unaffected protein masses for both LPL and HTGL, without overt immuno-dysfunction.

Effects of Histamine on Lipid Metabolic Disorder in Mice Loaded With Restraint Stress

The present study was conducted to investigate the effects of histamine on the lipid metabolic disorder in mice loaded with restraint stress. When Kun Ming (KM) mice were exposed to restraint stress for 20 h, the histamine level in both plasma and cerebral regions significantly increased (P<0.01). Moreover, when a lipid emulsion (10% Intralipid®) was injected intravenously into the mice, the elimination period of plasma triglyceride was prolonged in the restraint group. Plasma triglyceride was 523 ± 44 mg/dl at 35 min after the Intralipid® administration in the restraint stress group, while it was 436 ± 41 mg/dl in the restrained mice given histamine at a dose of 50 mg/kg. The improved plasma triglyceride metabolism was well explained by the observations of the significantly up-regulated hepatic triglyceride lipase (HTGL) activity and mRNA expression in response to histamine. These results suggested that the effects of stress-induced histamine on lipid metabolic disorder in mice loaded with restraint stress arose from its anti-stress action and promotion of lipase activity.

Effects of bezafibrate on dyslipidemia with cholestasis in children with familial intrahepatic cholestasis–1 deficiency manifesting progressive familial intrahepatic cholestasis

No appropriate pharmaceutical therapy has been established for dyslipidemia with cholestasis in progressive familial intrahepatic cholestasis (PFIC)–1. We evaluated the efficacy of bezafibrate in PFIC-1. We monitored the clinical presentation and lipoprotein metabolism of 3 patients, aged 3, 4, and 8 years, with FIC1 deficiency, manifesting PFIC-1, over 12 months of bezafibrate therapy. Pruritus was substantially alleviated in the 3 patients after initiation of bezafibrate. Cholestasis was alleviated in 2 of them. Serum high-density lipoprotein cholesterol and low-density lipoprotein cholesterol increased 1.6- to 2.0-fold and 1.1- to 1.2-fold, respectively; but the values remained low and normal, respectively. Serum lipoprotein X, which was at normal levels before treatment, was elevated to levels above the upper limit of the reference range. High serum triglyceride levels decreased by 15% to 30%, to normal levels, after treatment initiation. The activities of lipoprotein lipase and hepatic triglyceride lipase were increased, but those of high-density lipoprotein regulators remained unchanged. Liver expression of multidrug resistance protein–3, which regulates lipoprotein X synthesis, was enhanced by bezafibrate therapy. Bezafibrate treatment favorably affected pruritus, dyslipidemia, and cholestasis in PFIC-1.