Decreased Plasma Triglyceride Levels Research Articles

AAV-mediated hepatic LPL expression ameliorates severe hypertriglyceridemia and acute pancreatitis in Gpihbp1 deficient mice and rats

GPIHBP1 plays an important role in the hydrolysis of triglyceride (TG) lipoproteins by lipoprotein lipases (LPLs). However, Gpihbp1 knockout mice did not develop hypertriglyceridemia (HTG) during the suckling period but developed severe HTG after weaning on a chow diet. It has been postulated that LPL expression in the liver of suckling mice may be involved. To determine whether hepatic LPL expression could correct severe HTG in Gpihbp1 deficiency, liver-targeted LPL expression was achieved via intravenous administration of the adeno-associated virus (AAV)-human LPL gene, and the effects of AAV-LPL on HTG and HTG-related acute pancreatitis (HTG-AP) were observed. Suckling Gpihbp1-/- mice with high hepatic LPL expression did not develop HTG, whereas Gpihbp1-/- rat pups without hepatic LPL expression developed severe HTG. AAV-mediated liver-targeted LPL expression dose-dependently decreased plasma TG levels in Gpihbp1-/- mice and rats, increased post-heparin plasma LPL mass and activity, decreased mortality in Gpihbp1-/- rat pups, and reduced the susceptibility and severity of both Gpihbp1-/- animals to HTG-AP. However, the muscle expression of AAV-LPL had no significant effect on HTG. Targeted expression of LPL in the liver showed no obvious adverse reactions. Thus, liver-targeted LPL expression may be a new therapeutic approach for HTG-AP caused by GPIHBP1 deficiency.

Antihyperglycemic and Antidyslipidemic Effects of Artemisia arborescens Aqueous Extract on Streptozotocin-induced Diabetic Rats.

This study aimed to investigate the antidiabetic activity of Artemisia arborescens. Artemisia arborescens is an aromatic, medicinal, and endemic plant mostly found in the Mediterranean region. This plant is widely used as alternative medicine. The study was designed to examine the antihyperglycemic and antihyperlipidemic activities of Artemisia arborescens aqueous extract (AEAA) in normal and streptozotocin (STZ)- induced diabetic rats. The effect of AEAA (40 mg/kg and 80 mg/kg) on plasma glucose levels and plasma lipid profile was investigated in normal and STZ-induced diabetic rats. The plasma glucose levels were determined after a single (6 hours) and subchronic oral administration (7 days), and plasma lipid profiles were evaluated after both acute and subchronic oral administration. Additionally, the glycogen content in the liver, extensor digitorum longus (EDL), and soleus muscles was measured using a standard method. Moreover, the aqueous extract was tested for its 1.1-diphenyl-2- picrylhydrazyl (DPPH) radical-scavenging activity. In diabetic rats, AEAA oral administration (40 mg/kg and 80 mg/kg) produced a significant decrease in blood glucose levels after 7 days of oral administration (P<0.0001). Moreover, a significant decrease in plasma triglyceride levels was reported on the last day of treatment by AEAA (80 mg/kg) (P<0.05). Furthermore, a significant decrease in total cholesterol levels was observed after 7 days of AEAA oral administration in diabetic rats (P<0.01). Moreover, a significant increase in HDL-c concentration was noted after one week of AEAA (80 mg/kg) oral administration (P<0.001). In addition, AEAA oral administration (80 mg/kg) significantly increased the glycogen content in the liver and extensor digitorum longus (P<0.05). On the other hand, qualitative and quantitative phytochemical screenings revealed the presence of various compounds, such as polyphenols, flavonoids, and tannins. In summary, the study demonstrates that Artemisia arborescens oral administration exhibited a significant antihyperglycemic effect on diabetic rats and revealed a significant amelioration in lipid profile and glycogen content.

Studi of In Vivo Antidiabetic Activity of Namnam Leaves (Cynometra cauliflora) Extract in Sprague Dawley Rat

Various treatments for Type 2 Diabetes Mellitus (T2DM) aim to alleviate hyperglycemia. Although natural products have been extensively utilized, their mechanism of action and efficacy as antidiabetic agents, particularly for T2DM, has not been extensively assessed in vivo. In this research, the leaves of the Namnam (Cynometra cauliflora) were extracted and tested for their activity as an antidiabetic agent. Sprague Dawley rats aged 3.5-4 months, weighing 200-250 g, were used as the experimental model, with a total of 30 individuals. The rats were induced with a high-fat diet and 30% sucrose until their blood glucose concentration reached ≥ 120 mg/dL. Subsequently, the rats were divided into four groups (groups 1, 2, 3, and 4). Over 21 days, changes in blood glucose, triacylglycerol, glycogen, and blood plasma insulin levels were assessed. The results demonstrated that the methanol extract of Namnam leaves (NLME) effectively reduced blood glucose levels by 23-34%, decreased plasma triglyceride levels by 13-30%, and increased liver glycogen levels by 68-96% compared to the control group (Diabetes). Among all the parameters assessed, NLME exhibited similar performance to metformin, a commonly prescribed diabetes medication (p&lt;0.05). Furthermore, the study revealed that NLME exerted antidiabetic effects, particularly for T2DM, by promoting liver glycogen formation, enhancing insulin secretion control, facilitating glucose absorption by muscles, and restricting fat metabolism in the blood

A novel homozygous nonsense variant of LMF1 in pregnancy-induced hypertriglyceridemia with acute pancreatitis

Hypertriglyceridemia (HTG)-induced pancreatitis during pregnancy could lead to maternal and fetal death. However, its genetic bases are not fully understood, and its treatment strategies are yet to be established.Here we report a case with a novel homozygous nonsense variant of LMF1 in pregnancy-associated HTG with acute pancreatitis.Our patient had childhood-onset severe HTG that had been well-controlled by dietary management in the non-pregnant period with plasma triglyceride (TG) levels at around 200 mg/dL. Milky plasma was noted at the first-trimester pregnancy checkup, followed by a severe increase in plasma TG (10,500 mg/dL) that resulted in pancreatitis in the last trimester. The implementation of strict dietary fat restriction (less than 4 grams per day) reduced plasma TG levels and led to successful delivery. Exome sequencing revealed a novel homozygous nonsense variant in LMF1 (c.697C>T, p.Arg233Ter). The activities of lipoprotein lipase (LPL) and hepatic lipase in post-heparin plasma were not abolished but reduced. The use of pemafibrate decreased plasma TG levels with a concomitant increase in LPL activity.HTG in childhood or early pregnancy is commonly assumed to be polygenic in origin but should be regarded as a feature suggestive of monogenic hyperchylomicronemia. Adequate TG monitoring and dietary fat restriction should be implemented to prevent potentially lethal events of pancreatitis.

Effect of Parathyroidectomy on Metabolic Homeostasis in Primary Hyperparathyroidism.

Background: The benefits of parathyroidectomy on cardiovascular risk in primary hyperparathyroidism (PHPT) are controversial. This monocentric, observational, prospective study aimed to assess the effects of parathyroidectomy on glucose and lipid metabolism in classic or mild PHPT. Methods: Patients who underwent parathyroidectomy for classic (calcemia >2.85 mmol/L) or mild PHPT (calcemia ≤2.85 mmol/L) between 2016 and 2019 were included. A metabolic assessment was performed before and 1 year after parathyroidectomy. Patients with a history of diabetes were excluded. Results: Nineteen patients had classic and 120 had mild PHPT. Ninety-five percent were normocalcemic 6 months after surgery. Fasting plasma glucose and insulin levels decreased after parathyroidectomy in patients with mild PHPT (p < 0.001). HOMA-IR decreased after surgery in the overall population (p < 0.001), while plasma adiponectin concentrations increased in patients with both classic (p = 0.005) and mild PHPT (p < 0.001). Plasma triglyceride levels decreased significantly only in patients with classic PHPT (p = 0.021). Plasma PCSK9 levels decreased in patients with mild PHPT (p < 0.001). Conclusions: Parathyroidectomy for PHPT improves insulin resistance and decreases plasma triglyceride levels in classic PHPT and plasma PCSK9 levels in mild PHPT. Further studies are needed to better characterize the consequences of such metabolic risk factors’ improvements on cardiovascular events.

Lentinan Protects against Nonalcoholic Fatty Liver Disease by Reducing Oxidative Stress and Apoptosis via the PPARα Pathway.

Lentinan (LNT), a type of polysaccharide derived from Lentinus edodes, has manifested protective effects during liver injury and hepatocellular carcinoma, but little is known about its effects on nonalcoholic fatty liver disease (NAFLD). This study aimed to investigate whether LNT can affect the progression of NAFLD and the associated mechanisms. C57BL/6J mice were fed a normal chow diet or a high-fat diet (HFD) with or without LNT (6 mg/kg/d). AML12 cells were exposed to 200 μM palmitate acid (PA) with or without LNT (5 μg/mL). After 21 wk of the high-fat diet, LNT significantly decreased plasma triglyceride levels and liver lipid accumulation, reduced excessive reactive oxygen species production, and subsequently attenuated hepatic apoptosis in NAFLD mice. These effects were associated with increased PPARα levels, a decreased Bax/Bcl-2 ratio, and enhancement of the antioxidant defense system in vivo. Similar effects were also observed in cultured cells. More importantly, these protective effects of LNT on palmitate acid-treated AML12 cells were almost abolished by PPARα knockdown. In conclusion, this study demonstrates that LNT may ameliorate hepatic steatosis and decrease oxidative stress and apoptosis by activating the PPARα pathway and is a potential drug target for NAFLD.

The Effects of PPAR Agonists on Atherosclerosis and Nonalcoholic Fatty Liver Disease in ApoE-/-FXR-/- Mice.

Background Farnesoid X receptor (FXR), a bile acid–activated nuclear receptor, is a potent regulator of glucose and lipid metabolism as well as of bile acid metabolism. Previous studies have demonstrated that FXR deficiency is associated with metabolic derangements, including atherosclerosis and nonalcoholic fatty liver disease (NAFLD), but its mechanism remains unclear. In this study, we investigated the role of FXR in atherosclerosis and NAFLD and the effect of peroxisome proliferator-activated receptor (PPAR) agonists in mouse models with FXR deficiency.Methods En face lipid accumulation analysis, liver histology, serum levels of glucose and lipids, and mRNA expression of genes related to lipid metabolism were compared between apolipoprotein E (ApoE)−/− and ApoE−/−FXR−/− mice. The effects of PPARα and PPARγ agonists were also compared in both groups of mice.Results Compared with ApoE−/− mice, ApoE−/−FXR−/− mice showed more severe atherosclerosis, hepatic steatosis, and higher levels of serum cholesterol, low-density lipoprotein cholesterol, and triglycerides, accompanied by increased mRNA expression of FAS, ApoC2, TNFα, IL-6 (liver), ATGL, TGH, HSL, and MGL (adipocytes), and decreased mRNA expressions of CPT2 (liver) and Tfam (skeletal muscle). Treatment with a PPARα agonist, but not with a PPARγ agonist, partly reversed atherosclerosis and hepatic steatosis, and decreased plasma triglyceride levels in the ApoE−/−FXR−/− mice, in association with increased mRNA expression of CD36 and FATP and decreased expression of ApoC2 and ApoC3 (liver).Conclusion Loss of FXR is associated with aggravation of atherosclerosis and hepatic steatosis in ApoE-deficient mice, which could be reversed by a PPARα agonist through induction of fatty acid uptake, β-oxidation, and triglyceride hydrolysis.

Empagliflozin increases plasma levels of campesterol, a marker of cholesterol absorption, in patients with type 2 diabetes: Association with a slight increase in high-density lipoprotein cholesterol

Background and aimsSodium/glucose cotransporter 2 (SGLT2) inhibitors decrease plasma triglyceride levels and slightly increase low-density lipoprotein (LDL-c) and high-density lipoprotein cholesterol (HDL-c). However, the mechanisms underlying such changes in the blood lipid profile remain to be determined. We investigated how empagliflozin affects plasma markers of cholesterol absorption and synthesis, and evaluated the relationship between changes in these markers and blood lipids in patients with type 2 diabetes. Methods and resultsIn a randomized, active-controlled, open-label trial, 51 patients were randomly allocated in 2:1 ratio to receive empagliflozin 10 mg/day (n = 32) or standard therapy (n = 19) for 12 weeks. We measured plasma levels of lathosterol as a marker of cholesterol synthesis, and campesterol and sitosterol as markers of cholesterol absorption, at baseline and 12 weeks after treatment.In the empagliflozin group, serum HDL-c, but not LDL-c, significantly increased between baseline and 12 weeks (54.4 ± 16.3 vs. 58.8 ± 19.6 mg/dl; p = 0.0006), whereas in the standard therapy group, HDL-c and LDL-c remained unchanged. In the empagliflozin group, plasma campesterol also increased significantly (4.14 ± 1.88 vs. 4.90 ± 2.26 μg/ml, p = 0.0008), whereas no change in plasma campesterol or sitosterol was found in the control group. Although plasma lathosterol showed no change in the whole empagliflozin group, it decreased significantly in patients who were not taking statins. In statin non-users, plasma lathosterol decreased significantly after treatment with empagliflozin (2.71 ± 0.99 vs. 1.91 ± 0.99 μg/ml, p < 0.05). In the empagliflozin group, changes in plasma campesterol correlated positively with changes in HDL-c. ConclusionEmpagliflozin increases serum campesterol, a marker of cholesterol absorption, in patients with type 2 diabetes. This increase may be associated with SGLT2 inhibitor-induced increases in HDL cholesterol.

Activation of the PPAR‐alpha Receptor Increases Proteinuria in Young Obese Dahl Salt‐Sensitive Rats

Studies in the obese Dahl salt‐sensitive leptin receptor (SSLepRmutant) rats have shown that the progression of renal injury is associated with elevated plasma triglyceride levels and excessive renal lipid accumulation as early as 6 weeks of age. Previously, we observed that chronic treatment with gemfibrozil, an anti‐lipidemic drug via activation of PPAR‐α receptor, reduced plasma triglyceride levels, renal lipid accumulation, and renal fibrosis and improved renal function in old obese SSLepRmutant rats with chronic kidney disease (CKD). Since chronic treatment with gemfibrozil was effective in older animals and progressive proteinuria and renal injury occur prior to puberty in obese SSLepRmutant rats, the current study investigated the effects of gemfibrozil (200 mg/kg/day, orally) on the early progression of renal disease in young 4‐week old lean SS (n=6) and obese SSLepRmutant rats (n=6). Chronic treatment with gemfibrozil for 4 weeks significantly decreased plasma triglyceride levels by more than 50% in the young lean SS rats (115±18 vs. 47±13 mg/dL respectively), but only reduced these levels by 30% in young obese SSLepRmutant rats (417±99 vs. 287±127 mg/dL, respectively). Body weight and blood glucose levels were unaltered in both strains throughout the study. There were no significant differences in proteinuria between the obese SSLepRmutant and lean SS rats at baseline (27±9 vs. 4±1, respectively). However, proteinuria was significantly elevated in young obese SSLepRmutant rats compared to the values measured in young lean SS rats after 4 weeks (426±84 vs. 70±10 mg/day, respectively). While gemfibrozil treatment had no effect on protein excretion in older lean SS and obese SSLepRmutant rats, protein excretion was markedly increased in gemfibrozil‐treated young obese SSLepRmutant rats (722±114 mg/day). We did not observe any effect of gemfibrozil on protein excretion in young lean SS rats (82±21 mg/day). When examining glomerular injury (via PAS staining: % percentage of collapsed glomerular capillaries), chronic treatment with gemfibrozil had no effect on glomerular injury in these animals. Similar to the previous older animal study, young obese SSLepRmutant rats exhibited increased renal fibrosis (via Masson’s trichrome staining: % percentage of blue staining) when compared to the SS strain. Chronic treatment with gemfibrozil significantly reduced renal fibrosis in the young obese SSLepRmutant rats. Overall, these data may suggest that treatment with gemfibrozil in young obese SSLepRmutant rats increases the progression of proteinuria by reducing renal fibrosis indicating a potential side effect of gemfibrozil treatment in young animals. These data also indicate that additional experiments are needed to test the effects of gemfibrozil on renal hemodynamics, which may have an impact on the increased proteinuria observed in the young obese SSLepRmutant rats.Support or Funding InformationThis study was supported by GM104357 and DK109133.

Effect of water-extractive components from funazushi, a fermented crucian carp, on the activity of fibrinolytic factors.

Japanese fermented foods, including funazushi, have have been studied insufficiently. Related research into fermented products has led to the hope that they might have positive effects on blood circulation, including anti-thrombosis effects. The possible antithrombotic effects of funazushi on the fibrinolytic system were examined. The administration of extracts from funazushi increased the activity of plasmin and tissue plasminogen activators in the fibrinolytic system but decreased the activity of plasminogen activator inhibitor type-1 (PAI-1). This decrease was positively correlated with the decreased plasma triglyceride levels. Funazushi extract directly inhibited PAI-1 activity in vitro despite alimentary enzyme digestion, although direct PAI-1 inhibition was not observed in an extract from salted crucian carp. These results suggest that funazushi extracts are closely involved in the antithrombotic effects of the fibrinolytic system, and that they exert their effect through a reduction in PAI-1 activity. The findings also indicate that fermentation processing is necessary to achieve the antithrombotic effects of funazushi. © 2020 Society of Chemical Industry.

A Novel Acetyl-CoA Carboxylase 2 Selective Inhibitor Improves Whole-Body Insulin Resistance and Hyperglycemia in Diabetic Mice through Target-Dependent Pathways.

Excess intramyocellular lipid (IMCL) deposition in skeletal muscle is closely associated with insulin resistance. Pharmacological inhibition of acetyl-CoA carboxylase (ACC) 2 offers a promising approach to treat insulin resistance through stimulation of mitochondrial fatty acid oxidation (FAO) and reduction of IMCL deposition. Previously reported experimental ACC2 inhibitors exhibited plasma glucose-lowering effects in diabetic rodents. However, their antidiabetic action may be potentially biased by off-target effects on triglyceride metabolism or by neurologic side effects. In this study, we investigated a safety profile, target dependency of its action, and antidiabetic efficacy of compound 2e, a novel olefin derivative potent ACC2 selective inhibitor. Four-day administration of suprapharmacological dose of compound 2e did not exhibit any obvious side effects in Sprague-Dawley rats. In db/db mice, single administration of compound 2e led to significantly elevated FAO and reduced IMCL deposition in skeletal muscle. In ACC2 knockout mice, treatment with pharmacological doses of compound 2e did not reduce plasma triglyceride levels, whereas A-908292, a previously reported ACC2 inhibitor, caused a significant triglyceride reduction, showing that compound 2e was devoid of off-target triglyceride-lowering activity. Chronic treatment of db/db mice with compound 2e improved hyperglycemia but did not decrease plasma triglyceride levels. Additionally, compound 2e showed significant improvements of whole-body insulin resistance in the clamp study and insulin tolerance test. Collectively, compound 2e demonstrated a good safety profile and significant antidiabetic effects through inhibition of ACC2-dependent pathways. These findings provide further evidence that selective inhibition of ACC2 is an attractive strategy against insulin resistance and type 2 diabetes. SIGNIFICANCE STATEMENT: This study shows that pharmacological inhibition of acetyl-CoA carboxylase (ACC) 2 leads to significant improvements in whole-body glucose homeostasis, independently of off-target metabolic pathways and toxicity, which were observed in previously reported ACC2 inhibitors. These findings support the concept that ACC2-selective inhibitors will be a novel remedy for treatment of type 2 diabetes.

Transcriptional regulation of the AMP-activated protein kinase and glycolipid metabolism-related genes by insulin and glucagon in blunt snout bream (Megalobrama amblycephala): A comparative study

In this study, the effects of insulin and glucagon administration on the glycolipid metabolism of blunt snout bream (Megalobrama amblycephala) were investigated. Fish (average weight 49.5 ± 0.8 g) were intraperitoneally injected with a 0.9% saline solution, a bovine insulin (0.052 mg/kg body weight) and a bovine glucagon (0.075 mg/kg body weight), respectively. Then, samples were taken at 0, 1, 2, 4, 8 and 12 h post injection. The results showed that insulin load induced a significant decrease of plasma glucose level with the minimum observed at 1 h, while the opposite was true after glucagon injection (the highest value was attained at 4 h). After that, plasma glucose levels gradually returned to the normal value. Plasma triglycerides (TG) levels significantly declined during the first 2 h after insulin injection. Then, it increased significantly from 2 to 4 h, and gradually returned to the normal value. The glucagon administration significantly decreased plasma TG levels with the minimum value found at 8 h post-injection. Then, it significantly increased and returned to the basal value with further increasing times. Insulin injection resulted in a significantly increased liver glycogen and lipid contents, which peaked at 2 and 1 h, respectively. However, glucagon injection induced a significant decrease of both parameters. Subsequently, they gradually returned to the normal values. Besides, insulin load significantly decreased the transcriptional levels of AMPKα1, AMPKα2, PEPCK, FBPase, G6pase, PPARα, CPT Ⅰ and ACO during the first 4 h. However, those of GLUT2, GK, PK, SREBP1, FAS and ACCα all increased significantly during the 2–4 h. After the glucagon injection, the transcriptional values of AMPKα1, AMPKα2, PEPCK, FBPase, G6pase, PPARα, CPT I and ACO all increased significantly during the first 8 h, whereas the opposite was true for the remaining indicators during the first 4 h. Overall, exogenous insulin and glucagon significantly affected the glycolipid metabolism of Megalobrama amblycephala. Insulin injection significantly decreased plasma glucose level, but activated AMPK, thus promoting glucose transportation, glycogenesis, glycogenesis and lipogenesis coupled with the depression of gluconeogenesis and fatty acid oxidation, whereas the opposite was true after the glucagon load.

Hypoxic Training Improves Normoxic Glucose Tolerance in Adolescents with Obesity.

This study aimed to test whether environmental hypoxia could potentiate the effects of exercise training on glucose metabolism and insulin sensitivity. Fourteen adolescents with obesity were assigned to 6 wk of exercise training either in normoxic or in hypoxic conditions (FiO2 15%). Adolescents trained three times per week for 50-60 min, including endurance and resistance exercises. Oral glucose tolerance test, blood and morphological analyses, and physical performance tests were performed before and after the training period. After training, hypoxia, but not normoxia, decreased the area under the curve of plasma insulin (-49%; P = 0.001) and glucose levels (-14%; P = 0.005) during oral glucose tolerance test. Decreased plasma triglycerides levels (P = 0.03) and increased maximal aerobic power (P = 0.002), work capacity at 160 bpm (P = 0.002), and carbohydrate consumption during exercise (P = 0.03) were measured only in the hypoxic group. Hypoxic exercise training was particularly efficient at improving glucose tolerance and insulin response to a glucose challenge in adolescents with obesity. These results suggest that exercise training in hypoxia could be an interesting strategy against insulin resistance and type 2 diabetes development in adolescents with obesity.

Quercetin Lowers Plasma Triglycerides Accompanied by White Adipose Tissue Browning in Diet-Induced Obese Mice.

Obesity and dyslipidemia are major risk factors for the development of cardiovascular diseases (CVD). Quercetin, a natural flavonoid, lowers plasma triglycerides (TG) in human intervention studies, and its intake is associated with lower CVD risk. The aim of this study was to elucidate the mechanism by which quercetin lowers plasma TG levels in diet-induced obesity. C57Bl/6J mice received a high-fat diet (45% of calories derived from fat) with or without quercetin (0.1% w/w) for 12 weeks. Quercetin decreased plasma TG levels from nine weeks onwards (−19%, p < 0.05), without affecting food intake, body composition, or energy expenditure. Mechanistically, quercetin did not reduce intestinal fatty acid (FA) absorption. Rather, quercetin induced a slight reduction in liver Apob expression (−13%, p < 0.05), which suggests decreased very-low density lipoprotein-TG production. Interestingly, quercetin also markedly increased the uptake of [3H]oleate, which was derived from glycerol tri[3H]oleate-labeled lipoprotein-like particles by subcutaneous white adipose tissue (sWAT, +60%, p < 0.05). Furthermore, quercetin also markedly increased mRNA expression of Ucp1 (+229%, p < 0.05) and Elovl3 (+138%, p < 0.05), specifically in sWAT. Accordingly, only quercetin-treated animals showed uncoupling protein-1 protein-positive cells in sWAT, which is fully compatible with increased browning. Taken together, the TG-lowering effect of quercetin may, at least in part, be due to increased TG-derived FA uptake by sWAT as a consequence of browning.

Study of Hypolipidemic and Antioxidant Activities of Anvillea radiata Coss &amp; Durieu in Diabetic Rats

Objective: To evaluate the hypolipidemic and antioxidant effects of aqueous extract leaves of Anvillea radiata (AEL of A. radiata) in normal and streptozotocin (STZ) induced diabetic rats. In addition, the determination of total polyphenol and total flavonoid contents in the AEL of A. radiate was performed. Methods: The effects of oral administration of AEL of A. Radiata (10 mg/kg) on the plasma total cholesterol (TC), triglyceride (TG) and high-density lipoprotein-cholesterol (HDL-C) concentrations were measured in both normal and diabetic rats. The antioxidant capacity was realized by the method of DPPH. Total polyphenol, as well as, flavonoid contents of the AEL of A. radiata were determined by Folin-Ciocalteu method and colorimetric AlCl3 method, respectively. Results: AEL of A. radiate (10 mg/kg) showed a strong hypolipidemic effect both in normoglycaemic and in STZ rats after 15 days of daily treatment. In normal rats, AEL of A. radiata induced a significant decrease in plasma triglyceride levels (p<0.0001). Moreover, plasma cholesterol total levels reduced significantly (p<0.05; p<0.0001) both in normal and diabetic rats, respectively. In contrast, plasma HDL-C levels showed a significant increase (p<0.05; p<0.01) both in normal and in STZ induced diabetic rats, respectively. On the other side, AEL of A. radiata showed important antioxidant activity and revealed the inhibitory concentration of 50% of free radicals (IC50) (IC50=343.41 mg/ml). Concerning the quantitative determination of total polyphenol and flavonoid contents, which were equal to 70.28 mg of gallic acid equivalent per gram of extract (mg EAG/g) and 16.38 mg of quercetin equivalent per gram of extract (EQ/g), respectively. Conclusion: AEL of A. radiata (10 mg/kg) shows the potential hypolipidemic and antioxidant effects in both normal and STZ-induced diabetic rats. Keywords: A. radiata, streptozotocin, total cholesterol, triglycerides, flavonoids, anti-oxidants.

Hepatocyte miRNA‐21‐Deficiency Promotes Hepatic Lipid Accumulation but Ameliorates Alcohol‐Induced Liver Injury by Targeting DUSP16

BackgroundAccumulation of lipid droplets and inflammatory cell infiltration in the liver is the pathophysiological hallmark of alcoholic liver disease (ALD). The cell‐type specific role of miR‐21 in ALD remains unknown due to the lack of cell‐type specific knockout mice. The current study aims at elucidating the pathophysiological role of miR‐21 in ALD using our newly generated hepatocyte specific miR‐21 knockout mice.MethodsWe generated a new mouse model for hepatocyte specific deletion of miR‐21 (Hep‐KO). To induce alcoholic steatosis, Hep‐KO and their wild‐type (WT) littermates were fed with isovolumetric/isocaloric control liquid diet or Lieber‐DeCarli ethanol liquid diet at different concentrations (1% to 6%) for 4 weeks followed by a single binge. Markers of steatosis, liver injury and inflammation were assessed. Lipidomics and metabolomics were conducted. Other methods: liver histology, 3′UTR luciferase reporter, qPCR, Western blots, Oil O red staining.ResultsLiver miR‐21 RNA levels were highly induced in WT mice fed the ethanol diet compared with mice fed the control diet. Moreover, miR‐21 levels were markedly upregulated in human patients with alcoholic cirrhosis vs normal controls, demonstrating their roles in the pathogenesis of ALD. Hep‐KO mice fed the ethanol diet had increased hepatic triglyceride (TG) but decreased plasma TG levels, which was associated with increased lipogenesis (FASN, SCD1 and SREBP protein expression) but decreased VLDL secretion (MTTP). Lipidomics analysis revealed increased TG but decreased phosphatidyl cholines (PC) and phosphatidyl ethanolamines (PE) lipid species in Hep‐KO vs WT mice. Interestingly, inflammation was attenuated in Hep‐KO, as evident by the decreased serum AST and ALT levels, and reduced expression of key hepatic pro‐inflammatory (Il‐6, Ccr2, MIP1a, LyG6) genes. At the cellular level, MAPKs, AMPK and PPARs signaling pathways were assessed to determine the key regulatory role of miR‐21 in steatosis and inflammation, which showed that the activation of P38 and JNK were suppressed in Hep‐KO. Using TargetScan, microrna and miRanda, we predicted a conserved miR‐21 seed match region in mouse and human DUSP16 3′UTRs; a gene known as a phosphatase of P38 and JNK. Transfection of miR‐21 mimics reduced the DUSP16 protein in HepG2 and Hepa1 cells. In addition, the mouse DUSP16 3′UTR containing the miR‐21 seed region was cloned into a luciferase reporter and miR‐21 mimic inhibited DUSP16 3′UTR activity in a dose‐dependent fashion, which was relieved when the miR‐21 seed region was mutated. Furthermore, DUSP16 protein expression was down‐regulated in patients with alcoholic liver cirrhosis, where miR21, P‐P38 and P‐JNK levels were elevated.ConclusionHepatocyte miR‐21‐deficiency promotes alcoholic steatosis, but ameliorates liver injury and inflammation through the miR‐21/DUSP16/P38 pathway. Our work provides novel insights into the understanding of the molecular mechanism of non‐coding RNAs as key regulators in alcoholic liver disease.Support or Funding InformationGrant support: NIH R01DK104656, R01DK080440, R01ES025909, R21AA022482, R21AA024935, VA Merit Award 1I01BX002634.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of rich resistant starch snack on MCP- 1 promoter methylation and triglycerides levels in type 2 diabetes mellitus patients

Type 2 diabetes mellitus (T2DM) is closely related to inflammation. One of inflammation marker in T2DM is monocyte chemoattractant protein-1 (MCP-1). Previous research suggests that MCP-1 promoter methylation correlated significantly with plasma triglycerides levels (TG) in T2DM. Some studies state that TG levels in T2DM can be controlled through consumption of diets containing resistant starch. This study aimed to investigate the effect of high resistant starch snack on MCP-1 promoter methylation and triglycerides levels in type 2 diabetes mellitus. This study was a cross-over trial. A total of 19 T2DM subjects have been selected with the criteria of fasting blood glucose levels (GDP)>126 mg/dL, aged 40-60 years, and duration of DM at least 1 year. Subject consume snack as much as 32 g/day with the resistant starch content are 4.25 g for 4 weeks. Data collection and blood retrieval was doing before and after the intervention. The analysis of MCP-1 promoter methylation was performed by methylated specific-PCR (MS-PCR) using DNA samples extracted from mononuclear cells, whereas TG levels analysis performed by the enzymatic colorimetric method (DiaSys Kit) using blood plasma. Statistic analysis was performed by Fisher Exact test for methylation data, paired t-test and unpaired t test for TG levels, and Spearman correlation test for the correlation between variabels (p 0.05). Plasma triglyceride levels after intervention decreased, but not significant statistically. The correlation between MCP-1 promoter methylation and plasma triglyceride levels was significant. This study concludes that the giving of rich resistant starch snacks intervention does not affect MCP-1 promoter methylation changes significantly. This intervention can lead to decrease plasma triglyceride levels subjects, but not statistically significant.

Pemafibrate: First Global Approval.

Pemafibrate (Parmodia®) is a novel, highly selective peroxisome proliferator-activated receptor (PPAR)-α modulator (SPPARM). It acts by binding to PPAR-α and regulating the expression of target genes that modulate lipid metabolism, thereby decreasing plasma triglyceride levels and increasing high-density lipoprotein cholesterol levels. Developed by Kowa Company, Ltd., oral pemafibrate has been approved in Japan for the treatment of hyperlipidaemia (including familial hyperlipidaemia). This article summarizes the milestones in the development of pemafibrate leading to this first global approval for hyperlipidaemia.

PPAR in Cardiovascular Disorders.

Peroxisome proliferation-activated receptors (PPARs) are ligand-inducible transcription factors that, upon binding their ligands, translocate into the nucleus, where they regulate transcription of numerous genes that have the peroxisome proliferator response element (PPRE) in the promoter region [1]. In humans, there are 3 PPAR isoforms: PPAR-α, PPAR-β/δ, and PPAR-γ. The isoforms have partially overlapping spectra of activity and are differently expressed in organs and tissues [2]. PPAR-α is expressed mostly in tissues characterized by high catabolic activity, including skeletal muscle, liver, proximal tubular cells in kidneys, and brown fat. This PPAR isoform regulates components of β-oxidation pathway, enzymes, and transporters involved in fatty acid metabolism and promotes lipolysis and fatty acid oxidation. PPAR-α can be activated by fatty acids, prostaglandins, fibric acid derivatives (fibrates), and a number of recently developed specific agonists. Activation of PPAR-α has a beneficial effect on processes involved in the development of atherosclerosis, as it decreases plasma triglyceride levels, increases high density lipoprotein cholesterol, and reduces inflammatory response. Therefore, PPAR-α agonists gain attention as potential components of antiatherosclerotic therapy [3, 4]. PPAR-β/δ is expressed in many organs and tissues, with relatively high levels present in skeletal muscle, liver, kidney, and macrophages. It is activated by fatty acids and carbaprostacyclin, stimulates fatty acid oxidation, and improves insulin sensitivity in insulin-resistant animal models. This isoform is also known to have potential antiatherosclerotic properties and is considered for treatment of cardiovascular disorders [5, 6]. PPAR-γ is mainly expressed in white and brown fat and can also be found in other organs and tissues, including liver, kidney, and immune cells. It is activated by fatty acids implicated in regulation of glucose homeostasis, lipid metabolism, and adipogenesis. Synthetic PPAR-γ agonists, thiazolidinediones, such as pioglitazone and rosiglitazone, are currently used as insulin sensitizers but can have a broader therapeutic potential for treatment of conditions associated with increased cardiovascular risk [7]. Therefore, PPARs have a wide spectrum of biological activities relevant to prevention and treatment of cardiovascular diseases. Moreover, the availability of natural and synthetic small molecule agonists, many of them being relatively well studied by now, makes PPARs attractive therapeutic targets. To date, PubMed literature database delivers more than 3300 articles found by key words “PPAR” + “cardiovascular”. In this special issue, we are happy to present several important works revealing various aspects of PPAR involvement in cardiovascular conditions. The importance of PPAR-α signalling for regulation of cardiomyocyte metabolism is highlighted by the research articles of E. Czarnowska with coauthors, who studied the correlation of PPAR-α activity and cardiomyocyte function during heart failure, and J. Yang with coauthors, who demonstrated that PPAR-α upregulation mediated the effect of testosterone replacement on cardiac metabolic remodelling after myocardial infarction. G. Barreto-Torres with S. Javadov and W.-Y. Wei with coauthors presented the links between PPAR activation and the key cellular signalling network, which includes the AMPK and AKT pathways and regulates cellular metabolism, growth, and response to stress. Another evidence of anti-inflammatory properties of pioglitazone in patients with drug eluting stents is presented by Z. Wang and coauthors. H.-J. Liu and coauthors provide evidence for the critical role of PPAR-γ in cardiac fibrosis, and A. Pleskovic with coauthors reported that PPAR-γ polymorphisms have a minor effect on atherosclerosis markers in diabetic patients. K.-D. Wagner with coauthors demonstrates that inducible vascular-specific overexpression of PPAR-β/δ causes cardiac hypertrophy. Finally, a review article of W.-S. Lee and J. Kim provides an overview of the roles of PPARs in the heart. Together, the works collected in this special issue add to our growing knowledge on the PPARs and their activators in the context of cardiovascular disorders. Alexander N. Orekhov Nigora Mukhamedova Ekaterina A. Ivanova Manfredi Rizzo

Discovery of a Novel Series of Indolyl Hydrazide Derivatives as Diacylglycerol Acyltransferase‐1 Inhibitors

A novel series of hydrazide derivatives were synthesized as potential diacylglycerol acyltransferase (DGAT) inhibitors. Among them, compounds 8u and 8v exhibited selective and potent DGAT‐1 inhibitory activities. In addition, compound 8u dose‐dependently inhibited triglyceride synthesis in HepG2 cell lines. Furthermore, treatment with compound 8u for an oral lipid tolerance test showed a significant decrease in plasma triglyceride levels compared with vehicle‐treated control animals, indicating delayed absorption of triglyceride after an acute lipid challenge.