Obviation of dyslipidemia by garlic oil and its organosulfur compound,diallyl disulphide,in experimental animals

Background and objectivesGarlic and its number of preparations are known to be effective for treatment of dyslipidemia, but the data about the specific active constituents of the garlic on the possible therapeutic value is scarce. Therefore, the aim of this research was to evaluate the role of garlic oil (GO) and its active element, diallyl disulphide (DADS) for obviating dyslipidemia in animal model.MethodsHigh fat diet (HFD) was given to animals to induce dyslipidemia. Animals of HFD groups were fed with atherogenic diet for 15 days prior to treatment. Animals in their respective groups received vehicle, GO (50 and 100 mg/kg), and DADS (4.47 and 8.94 mg/kg) for five consecutive days. Lipid profiles were estimated in serum, oxidant/antioxidant and liver profile were measured in liver tissue homogenate (LTH).ResultsAnimals fed on HFD developed significant increase in the serum levels of triglycerides (TG), total cholesterol (TC), lactate dehydrogenase (LDL), malondialdehyde (MDA), glutathione peroxidase (GSHPx), glutathione (GSH), and glutathione disulfide (GSSG) that reduced significantly in groups that received GO and DADS treatments. Additionally, significant elevation in serum high density lipoprotein (HDL) level was observed in animals that received GO and DADS. Moreover, hepatic markers such as alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine transferase (ALT), that were abnormally altered by high fat diet, were significantly restored to almost normal values with GO and DADS treatments. Also, antioxidants such as superoxide dismutase (SOD), catalase (CAT), ferric reducing antioxidant power (FRAP), and total thiol (SH) levels in LTH were increased significantly in GO and DADS treated groups. When compared to DADS, GO showed better therapeutic effectiveness in terms of antihyperlipidemic and antioxidant properties.ConclusionIn hyperlipidemic rats, garlic and its principal active component, diallyl disulphide, were effective in avoiding dyslipidemia and neutralizing reactive free radicals induced by a high fat diet. It's an intriguing observation that GO has a larger therapeutic influence than its active constituent, DADS. These findings suggest that other constituents, in addition to GO's DADS, are involved in the compound's synergistic antihyperlipidemic and antioxidant activities.     

Antihyperlipidemic and antioxidant effects of feather protein hydrolysate in high‐fat diet‐fed mice

The hyperlipidemia is a serious health problem that increases the risk of many complications including cardiovascular disease. This study aims to evaluate the possible antihyperlipidemic effects of the feather protein hydrolysate (FPH) in a mice fed with a high‐fat diet (HFD)‐fed mice during 5 weeks. The FPH administration improved dose‐dependent lipid profile, as well as the liver and renal dysfunction indices in hyperlipidemic mice. The FPH also restored the antioxidant status in liver, kidney, and heart by lowering the lipid peroxidation and enhancing the antioxidant enzymes (catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase [SOD]). Moreover, the histological studies proved that FPH administration prevents hepatic steatosis, glomerular hyperfiltration risk, and cardiac muscle hypertrophy. Accordingly, the FPH is a promising novel medicinal ingredient for possible use in the hyperlipidemic treatment and related complications.     

Astaxanthin reduces hepatic lipid accumulations in high-fat-fed C57BL/6J mice via activation of peroxisome proliferator-activated receptor (PPAR) alpha and inhibition of PPAR gamma and Akt

We have previously reported that astaxanthin (AX), a dietary carotenoid, directly interacts with peroxisome proliferator-activated receptors PPARα and PPARγ, activating PPARα while inhibiting PPARγ, and thus reduces lipid accumulation in hepatocytes in vitro. To investigate the effects of AX in vivo, high-fat diet (HFD)-fed C57BL/6J mice were orally administered AX (6 or 30 mg/kg body weight) or vehicle for 8 weeks. AX significantly reduced the levels of triglyceride both in plasma and in liver compared with the control HFD mice. AX significantly improved liver histology and thus reduced both steatosis and inflammation scores of livers with hematoxylin and eosin staining. The number of inflammatory macrophages and Kupffer cells were reduced in livers by AX administration assessed with F4/80 staining. Hepatic PPARα-responsive genes involved in fatty acid uptake and β-oxidation were upregulated, whereas inflammatory genes were downregulated by AX administration. In vitro radiolabeled assays revealed that hepatic fatty acid oxidation was induced by AX administration, whereas fatty acid synthesis was not changed in hepatocytes. In mechanism studies, AX inhibited Akt activity and thus decreased SREBP1 phosphorylation and induced Insig-2a expression, both of which delayed nuclear translocation of SREBP1 and subsequent hepatic lipogenesis. Additionally, inhibition of the Akt-mTORC1 signaling axis by AX stimulated hepatic autophagy that could promote degradation of lipid droplets. These suggest that AX lowers hepatic lipid accumulation in HFD-fed mice via multiple mechanisms. In addition to the previously reported differential regulation of PPARα and PPARγ, inhibition of Akt activity and activation of hepatic autophagy reduced hepatic steatosis in mouse livers.     

Relationship between hepatic and mitochondrial ceramides: a novel in vivo method to track ceramide synthesis

Ceramides (CERs) are key intermediate sphingolipids implicated in contributing to mitochondrial dysfunction and the development of multiple metabolic conditions. Despite the growing evidence of CER role in disease risk, kinetic methods to measure CER turnover are lacking, particularly using in vivo models. The utility of orally administered ¹³C₃, ¹⁵N l-serine, dissolved in drinking water, was tested to quantify CER 18:1/16:0 synthesis in 10-week-old male and female C57Bl/6 mice. To generate isotopic labeling curves, animals consumed either a control diet or high-fat diet (HFD; n = 24/diet) for 2 weeks and varied in the duration of the consumption of serine-labeled water (0, 1, 2, 4, 7, or 12 days; n = 4 animals/day/diet). Unlabeled and labeled hepatic and mitochondrial CERs were quantified using liquid chromatography tandem MS. Total hepatic CER content did not differ between the two diet groups, whereas total mitochondrial CERs increased with HFD feeding (60%, P < 0.001). Within hepatic and mitochondrial pools, HFD induced greater saturated CER concentrations (P < 0.05) and significantly elevated absolute turnover of 16:0 mitochondrial CER (mitochondria: 59%, P < 0.001 vs. liver: 15%, P = 0.256). The data suggest cellular redistribution of CERs because of the HFD. These data demonstrate that a 2-week HFD alters the turnover and content of mitochondrial CERs. Given the growing data on CERs contributing to hepatic mitochondrial dysfunction and the progression of multiple metabolic diseases, this method may now be used to investigate how CER turnover is altered in these conditions.     

Hypocholesterolemic effects of fatty acid bile acid conjugates (FABACs) in mice

Fatty acid bile acid conjugates (FABACs) prevent and dissolve cholesterol gallstones and prevent diet induced fatty liver, in mice. The present studies aimed to test their hypocholesterolemic effects in mice. Gallstone susceptible (C57L/J) mice, on high fat (HFD) or regular diet (RD), were treated with the conjugate of cholic acid with arachidic acid (FABAC; Aramchol). FABAC reduced the elevated plasma cholesterol levels induced by the HFD. In C57L/J mice, FABAC reduced plasma cholesterol by 50% (p < 0.001). In mice fed HFD, hepatic cholesterol synthesis was reduced, whereas CYP7A1 activity and expression were increased by FABAC. The ratio of fecal bile acids/neutral sterols was increased, as was the total fecal sterol excretion. In conclusion, FABACs markedly reduce elevated plasma cholesterol in mice by reducing the hepatic synthesis of cholesterol, in conjunction with an increase of its catabolism and excretion from the body.     

Mesenteric adipose tissue B lymphocytes promote local and hepatic inflammation in non‐alcoholic fatty liver disease mice

Mesenteric adipose tissue (MAT) inflammation is associated with non‐alcoholic fatty liver disease (NAFLD), and immune cells play pivotal roles in the inflammation of adipose tissue. Here, we investigated the roles of MAT B lymphocytes in NAFLD. Mice fed with high‐fat diet (HFD) and normal diet (ND) were killed in time gradients (4, 8 and 12 weeks). Compared with ND‐fed mice, intra‐hepatic CD45⁺CD19⁺ B lymphocytes increased after 4 weeks (P < 0.01) of HFD feeding, and lasted until the 12th week, infiltrated earlier than CD45⁺CD3⁺ T lymphocytes and CD45⁺F4/80⁺ macrophages. The mRNA expression of tumour necrosis factor (TNF)‐α, interleukin (IL)‐6 and monocyte chemotactic protein (MCP)‐1 decreased in MAT of B^null HFD‐fed mice compared to that in wild‐type HFD‐fed mice, along with lesser macrophages. Mesenteric adipose tissue B cells from HFD‐fed mice promoted macrophage differentiation to type‐Ι macrophages and expression of pro‐inflammatory cytokines in vitro. Macrophages pre‐treated with MAT B cells from HFD‐fed mice showed elevated mRNA expression of IL‐6 and TNF‐α and declined IL‐10 levels in adipocytes compared to ND MAT B cell pre‐treated macrophages. Besides, internal near‐infrared scanning and external transwell assay showed that HFD MAT B cells migrated to the liver more than ND MAT B cells. High‐fat diet MAT B cells induced higher MCP‐1 and lower IL‐10 expression in primary hepatocytes compared to ND MAT B cells in co‐culture experiment. These data indicate that B lymphocytes infiltrate early in MAT during the development of NAFLD, which may not only promote MAT inflammation by regulating macrophages but also migrate to the liver and induce hepatocytes inflammation.     

Single-bulb garlic oil regulates toll-like receptors and Nrf2 cross-talk and IL-17 production in mice fed with high-fat diet

The present study aimed to evaluate the effect of single-bulb garlic oil (SGO) on toll-like receptors 3 and 4 (TLR3 and TLR 4) and nuclear erythroid factor-like 2 (Nrf2) signaling pathway resulted from a high-fat diet and its underlying mechanism. Twenty-four Balb/c mice allocated into six groups: 1) N: mice fed with standard chow; 2) HFD: mice fed a high-fat diet for 45 days without any treatment; 3) HFD + Simv: mice fed a high-fat diet for 45 days and treated with simvastatin; 4–6) HFD + SGO 100, 200, 400 (mice fed a high-fat diet for 45 days and treated with single-bulb garlic oil at dose: 100, 200, and 400 mg/kg body weight for 30 days), respectively. At the end of treatment, spleen and hepar were isolated. The flow cytometry analysis was performed to analyze the relative number of nrf2, superoxide dismutase (SOD), malondialdehyde (MDA), TLR3, TLR4 and interleukin (IL-17). The results showed that HFD induction significantly reduced Nrf-2 and antioxidant enzyme levels. Furthermore, HFD induction increased TLR3 and TLR4 signaling and IL-17 production. Interestingly, 200 mg/kg BW of SGO increased the relative number Nrf-2 followed by SOD and HO-1 elevation at a dose of 100 mg/kg BW. SGO100 notably decrease the relative number of TLR3 (CD11b⁺TLR3⁺) and TLR4 (CD11b⁺TLR4⁺). The production of IL-17 by CD4 and CD8 were also reduced after receiving SGO at 200 mg/kg BW. This study suggests that the protective effect of SGO treatment on HFD mice was achieved by modulating TLR-Nrf2 cross-talks and decreasing IL-17 production. Our findings support a potential beneficial role of SGO for treating metabolic disease caused by a high-fat diet.     

Calcium supplementation relieves high-fat diet-induced liver steatosis by reducing energy metabolism and promoting lipolysis

Nonalcoholic fatty liver disease (NAFLD) is a chronic disease affecting the health of many people worldwide. Previous studies have shown that dietary calcium supplementation may alleviate NAFLD, but the underlying mechanism is not clear. In this study investigating the effect of calcium on hepatic lipid metabolism, 8-week-old male C57BL/6J mice were divided into four groups (n = 6): (1) mice given a normal chow containing 0.5% calcium (CN0.5), (2) mice given a normal chow containing 1.2% calcium (CN1.2), (3) mice given a high-fat diet (HFD) containing 0.5% calcium (HFD0.5), and (4) mice fed a HFD containing 1.2% calcium (HFD1.2). To understand the underlying mechanism, cells were treated with oleic acid and palmitic acid to mimic the HFD conditions in vitro. The results showed that calcium alleviated the increase in triglyceride accumulation induced by oleic acid and/or palmitic acid in HepG2, AML12, and primary hepatocyte cells. Our data demonstrated that calcium supplementation alleviated HFD-induced hepatic steatosis through increased liver lipase activity, proving calcium is involved in the regulation of hepatic lipid metabolism. Moreover, calcium also increased the level of glycogen in the liver, and at the same time had the effect of reducing glycolysis and promoting glucose absorption. Calcium addition increased calcium levels in the mitochondria and cytoplasm. Taken together, we concluded that calcium supplementation could relieve HFD-induced hepatic steatosis by changing energy metabolism and lipase activity.     

Moringa peregrina leaf extracts produce anti-obesity,hypoglycemic, anti-hyperlipidemic,and hepatoprotective effects on high-fat diet fed rats

This present research investigated the anti-obesity and hepatoprotective effects of ethanolic Moringa peregrina leaf (MPLE) and bark extracts (MPBE), in the rats fed with a high-fat diet (HFD). Healthy male rats (n = 48) were randomly distributed to six groups (n = 8): control AIN-93 diet; HFD; HFD + MPBE bark extracts ((300 mg/kg); HFD + MPBE (600 mg/kg); HFD + MPLE (300 mg/kg); HFD + MPLE (600 mg/kg). HFD-fed rats in the Moringa peregrina (MP) treatment groups received orally administered MP leaf or bark extract daily for eight weeks. The results revealed that both doses of MP leaf extract significantly reduced HFD-induced increases in their food intake and the gained body weight, fat pad weights (visceral, subcutaneous, and epididymal), glucose and insulin plasma levels, and leptin and resistin serum levels in HFD-fed rats. Concomitantly, MP leaf extract improved glucose levels after oral or intraperitoneal glucose tolerance tests, reduced serum cholesterol, triglycerides, and the low-density lipoprotein LDL concentration, reduced hepatic triglycerides and cholesterol levels, and increased serum high-density lipoproteins HDL levels and triglycerides and cholesterol levels in fecal. Moreover, the administration of MPLE to HFD-fed rats improved liver architecture, reduced fat accumulation, reduced hepatic malondialdehyde, tumor necrosis factor-α, and interleukin-6 levels. Hepatic glutathione peroxidase, superoxide dismutase, and catalase activities were significantly increased. All observed effects were more pronounced in HFD-fed rats treated with a 600 mg/kg MP dose. However, neither dose of MPBE altered the measured markers in the HFD-fed rats. In conclusion, MPLE showed potential anti-obesity and hepatoprotective activity in HFD-induced obese rats, mediated by reduced lipid absorption, anti-hyperlipidemic effects, and hepatic antioxidant effects.     

Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet

To determine whether long-term melanocortinergic activation can attenuate the metabolic effects of a high fat diet, mice overexpressing an NH(2)-terminal POMC transgene that includes alpha- and gamma(3)-MSH were studied on either a 10% low-fat diet (LFD) or 45% high-fat diet (HFD). Weight gain was modestly reduced in transgenic (Tg-MSH) male and female mice vs. wild type (WT) on HFD (P < 0.05) but not LFD. Substantial reductions in body fat percentage were found in both male and female Tg-MSH mice on LFD (P < 0.05) and were more pronounced on HFD (P < 0.001). These changes occurred in the absence of significant feeding differences in most groups, consistent with effects of Tg-MSH on energy expenditure and partitioning. This is supported by indirect calorimetry studies demonstrating higher resting oxygen consumption and lower RQ in Tg-MSH mice on the HFD. Tg-MSH mice had lower fasting insulin levels and improved glucose tolerance on both diets. Histological and biochemical analyses revealed that hepatic fat accumulation was markedly reduced in Tg-MSH mice on the HFD. Tg-MSH also attenuated the increase in corticosterone induced by the HFD. Higher levels of Agrp mRNA, which might counteract effects of the transgene, were measured in Tg-MSH mice on LFD (P = 0.02) but not HFD. These data show that long-term melanocortin activation reduces body weight, adiposity, and hepatic fat accumulation and improves glucose metabolism, particularly in the setting of diet-induced obesity. Our results suggest that long-term melanocortinergic activation could serve as a potential strategy for the treatment of obesity and its deleterious metabolic consequences.     

Efficacy of azelaic acid on hepatic key enzymes of carbohydrate metabolism in high fat diet induced type 2 diabetic mice

Azelaic acid (AzA), a C9 linear α,ω-dicarboxylic acid, is found in whole grains namely wheat, rye, barley, oat seeds and sorghum. The study was performed to investigate whether AzA exerts beneficial effect on hepatic key enzymes of carbohydrate metabolism in high fat diet (HFD) induced type 2 diabetic C57BL/6J mice. C57BL/6J mice were fed high fat diet for 10 weeks and subjected to intragastric administration of various doses (20 mg, 40 mg and 80 mg/kg BW) of AzA daily for the subsequent 5 weeks. Rosiglitazone (RSG) was used as reference drug. Body weight, food intake, plasma glucose, plasma insulin, blood haemoglobin (Hb), blood glycosylated haemoglobin (HbA1c), liver glycolytic enzyme (hexokinase), hepatic shunt enzyme (glucose-6-phosphate dehydrogenase), gluconeogenic enzymes(glucose-6-phosphatase and fructose-1,6-bisphosphatase), liver glycogen, plasma and liver triglycerides were examined in mice fed with normal standard diet (NC), high fat diet (HFD), HFD with AzA (HFD + AzA) and HFD with rosiglitazone (HFD + RSG). Among the three doses, 80 mg/kg BW of AzA was able to positively regulate plasma glucose, insulin, blood HbA1c and haemoglobin levels by significantly increasing the activity of hexokinase and glucose-6-phosphate dehydrogenase and significantly decreasing the activity of glucose-6-phosphatase and fructose-1,6-bisphosphatase thereby increasing the glycogen content in the liver. From this study, we put forward that AzA could significantly restore the levels of plasma glucose, insulin, HbA1c, Hb, liver glycogen and carbohydrate metabolic key enzymes to near normal in diabetic mice and hence, AzA may be useful as a biomaterial in the development of therapeutic agents against high fat diet induced T2DM.     

Saudi date cultivars' seed extracts inhibit developing hepatic steatosis in rats fed a high-fat diet

This research aim was to assess the impact of the seed extracts of the date cultivars (Qatara, Barhi, and Ruthana) on rat’s liver steatosis, oxidative stress, and inflammation triggered by feeding a high-fat diet (HFD). The experimental design was based on random partitioning into two groups; one that received the standard diet and another that received the HFD diet. The HFD rats were orally administered Lipitor or date seed extracts at 300 or 600 mg/kg/day for 4 weeks. Accordingly, feeding rats HFD significantly increased body and liver weights, hepatic and serum lipid levels, glucose, insulin, HOMA-IR, liver function enzymes, and inflammation markers, and decreased oxidative stress enzymes. Oral administration of Barhi and Ruthana date seed extracts significantly decreased body and liver weights. Serum and liver total cholesterol TC, Triglycerides TGs, and free fatty acids FFAs were also decreased as were AST, ALT, MAD, leptin, and CRP, with a concomitant increase in SOD, GSH, and CAT. Furthermore, similar to Lipitor, oral administration of the extracts reduced inflammation markers such as TNF-α, serum CRP, IL-6, IL-1β, and leptin while increasing IL-10 and adiponectin levels. Histological observation revealed that extract administration improved hepatocyte and parenchymal structures and decreased lipid deposition. In conclusion, both Barhi and Ruthana seed extracts showed strong hepatoprotective, anti-inflammatory, and antioxidant effects against HFD-induced liver steatosis. And date seeds have other beneficial potential for prevention and treatment of various diseases, which can be studied in the future.     

Promising role of ferulic acid,atorvastatin and their combination in ameliorating high fat diet-induced stress in mice

AimsThe present study evaluated a comparative and combined hepatoprotective effect of atorvastatin (AS) and ferulic acid (F) against high fat diet (HFD) induced oxidative stress in terms of hyperlipidemia, anti-oxidative status, lipid peroxidation and inflammation.Main methodsMale Swiss albino mice were given a diet containing high fat (H) (23.9% wt/wt), supplemented with AS (10 mg/kg) or F (100 mg/kg) and both (10 and 100 mg/kg) for 8 weeks. The control mice (C) were fed with normal diet.Key findingsThe H mice exhibited increased body weight; hyperlipidemia; serum level of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6); hepatic lipid profile; lipid accumulation; reactive oxygen species (ROS) of hepatocytes, lipid peroxidation and liver antioxidant capacity was decreased. Immunofluorescent and Western blot assay revealed activation of nuclear factor kappa B (NF-κB) signaling pathway. The addition of F or AS and both in the diet significantly counteracted HFD induced body weight gain; hyperlipidemia; TNF-α, IL-6; hepatic lipid profile; fatty infiltration; NF-κB signaling pathway; ROS; lipid peroxidation and moreover elevated levels of hepatic antioxidant enzymes activity were observed.SignificanceSimultaneous treatment with AS, F and their combination protected against HFD induced weight gain and oxidative stress. The protection may be attributed to the hypolipidemic and free radical scavenging activity of AS or F and their combination. This study illustrates that AS and F have relatively similar hypolipidemic, antioxidative, anti-inflammatory actions and the AS + F combination along with HFD has shown outstanding effects as compared to other treated groups.     

Synthesis and antihyperlipidemic activity of novel coumarin bisindole derivatives

A series of novel coumarin bisindole heterocycles were synthesized following an uncommon method and evaluated for their antihyperlipidemic activity in hyperlipidemic hamster model. Among 12 compounds tested, the compound 5e showed potent antihyperlipidemic activity and was found to decrease the plasma triglyceride levels (TG) by 55%, total cholesterol (TC) by 20%, accompanied by an increase in HDL-C/TC ratio by 42% in hyperlipidemic rats to a greater degree than some of the reference statins.     

Role of Pregnane X Receptor in Obesity and Glucose Homeostasis in Male Mice

Clinical obesity is a complex metabolic disorder affecting one in three adults. Recent reports suggest that pregnane X receptor (PXR), a xenobiotic nuclear receptor important for defense against toxic agents and for eliminating drugs and other xenobiotics, may be involved in obesity. Noting differences in ligand specificities between human and mouse PXRs, the role of PXR in high fat diet (HFD)-induced obesity was examined using male PXR-humanized (hPXR) transgenic and PXR-knock-out (PXR-KO) mice in comparison to wild-type (WT) mice. After 16 weeks on either a control diet or HFD, WT mice showed greater weight gain, whereas PXR-KO mice gained less weight due to their resistance to HFD-induced decreases in adipose tissue peroxisome proliferator-activated receptor α and induction of hepatic carnitine palmitoyltransferase 1, suggesting increased energy metabolism. Interestingly, control-fed PXR-KO mice exhibited hepatomegaly, hyperinsulinemia, and hyperleptinemia but hypoadiponectinemia and lower adiponectin receptor R2 mRNA levels relative to WT mice. Evaluation of these biologic indicators in hPXR mice fed a control diet or HFD revealed further differences between the mouse and human receptors. Importantly, although HFD-fed hPXR mice were resistant to HFD-induced obesity, both PXR-KO and hPXR mice exhibited impaired induction of glucokinase involved in glucose utilization and displayed elevated fasting glucose levels and severely impaired glucose tolerance. Moreover, the basal hepatic levels of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 were increased in hPXR mice compared with WT mice. Altogether, although the mouse PXR promotes HFD-induced obesity, the hPXR mouse carries a genetic predisposition for type 2 diabetes and thus provides a model for exploring the role of human PXR in the metabolic syndrome.     

Gamma-glutamyl carboxylated Gas6 facilitates the prophylactic effect of vitamin K in inhibiting hyperlipidemia-associated inflammatory pathophysiology via arresting MCP-1/ICAM-1 mediated monocyte-hepatocyte adhesion

Role of growth arrest-specific 6 (Gas6), member of vitamin K (VK)-dependent protein family in hyperlipidemia-associated inflammation remains unresolved. To address this, blood samples were collected from hyperlipidemic subjects and age-matched healthy controls and observed that gamma-glutamyl carboxylated Gas6 (Gla-Gas6) but not total Gas6 were significantly lower while pro-inflammatory markers, MCP-1 and ICAM-1 were remarkably higher in hyperlipidemic subjects compared to control. Correlation analyses demonstrated that Gla-Gas6 levels were inversely correlated with MCP-1 and ICAM-1 but positively with plasma VK in hyperlipidemic subjects but not in control. This suggests that boosting VK level might ameliorate the hyperlipidemia-associated inflammatory pathophysiology via augmenting Gla-Gas6. Further studies with high fat diet (HFD)-fed mice demonstrated that VK supplementation (1, 3, and 5 µg/kg BW, 8 weeks) dose-dependently reduced both hepatic and plasma levels of MCP-1 and ICAM-1 while elevating that of Gla-Gas6 but not total Gas6 in HFD-fed mice. Cell culture studies with gamma-glutamyl carboxylase (enzyme causes VK-dependent carboxylation of Gas6) knockdown hepatocytes and monocytes dissected the direct role of Gla-Gas6 in inhibiting high palmitic acid (0.75 mM)-induced inflammation via arresting MCP-1/ICAM-1 mediated hepatocyte-monocyte adhesion. The present study demonstrated an important role of Gla-Gas6 in facilitating the prophylactic effect of VK against hyperlipidemia associated inflammation.     

Trichinella spiralis infection ameliorated diet-induced obesity model in mice

Obesity is an increasingly prevalent disease worldwide, and genetic and environmental factors are known to regulate the development of obesity and associated metabolic diseases. Emerging studies indicate that innate and adaptive immune cell responses in adipose tissue play critical roles in the regulation of metabolic homeostasis. Parasitic helminths are the strongest natural inducers of type 2 inflammatory responses, and several studies have revealed that helminth infections inversely correlate with metabolic syndrome. Hence, this study investigated whether helminth infections could have preventative effects on high fat diet-induced obesity. Female C57BL/6 mice were maintained on either a low fat diet (LFD, 10% fat) or a high fat diet (HFD, 60% fat) for 6 weeks after Trichinella spiralis infection. The mice were randomly divided into four groups and were fed a normal diet, LFD, LFD after T. spiralis infection (Inf + LFD), a high fat diet (HFD), or HFD after T. spiralis infection (HFD + inf). All groups were assayed for body weight, food efficiency ratio (FER), total body weight gain (g)/total food intake amount (g) fat weight, and blood biochemical parameters. Our data indicate that the HFD + inf group significantly reduced body weight gain, fat mass, total cholesterol, and FER. Analysis of immune cell composition by flow cytometry revealed that T. spiralis promoted strong decreases in proinflammatory adipose macrophages (F4/80⁺CD11c⁺) and T cells. The alterations in microbiota from fecal samples of mice were analyzed, which showed that T. spiralis infection decreased the ratio of Firmicutes to Bacteriodetes, thereby restoring the previously increased ratio of Firmicutes to Bacteriodetes in HFD-fed mice. Moreover, elimination of T. spiralis retained the protective effects in the HFD-fed obese mice whereas flubendazole (FLBZ) treatment increased levels of the families Lachnospiraceae and Ruminococcaceae. In summary, we provided novel data suggesting that helminth infection protects against obesity and the protection was closely related to M2 macrophage proliferation, an inhibiting proinflammatory response. In addition, it alters the microbiota in the gut.     

Hepatoprotective and antioxidant activity of N-Trisaccharide in different experimental rats

ObjectivesTo investigate the hepatoprotective, antioxidant and antihyperlipidemic effect of N-Trisaccharide isolated from Cucumis prophetarum (L.) on different experimental rats.MethodsN-Trisaccharide (25 and 50 mg/kg.b.w), silymarin (25 mg/kg) and glibenclamide (25 mg/kg) was orally administered once daily for 28 days and toxicity evaluation studies were carried out. Liver damage was assessed by determining DNA damage, serum enzyme activities and hepatic histopathology of carbon tetrachloride (CCl₄) induced hepatic injury in rats. Enzymatic and non enzymatic antioxidant levels in liver and kidney were determined and biochemical parameters such as, serum lipid profile, renal function markers were estimated in type 2 diabetic rats.ResultsDNA fragmentation analysis revealed the protective effect of N-Trisaccharide on liver DNA damage. Histopathological studies indicated that CCl₄-induced liver injury was less severe in N-Trisaccharide (25 and 50 mg/kg) treated group. Given at the above doses conferred significant protection against the hepatotoxic actions of CCl₄ in rats, reducing serum markers like SGOT, SGPT, ALP, creatinine and urea levels back to near normal (p < 0.05) compared to untreated rats. In diabetic rats, N-Trisaccharide treatment significantly reversed abnormal status of enzymatic and non-enzymatic antioxidants levels to near normal. Also, serum lipids such as TG, TC, LDL-C and VLDL-C levels were significantly (p < 0.05) reduced compared to diabetic untreated rats.ConclusionPresent study results confirm that N-Trisaccharide possesses significant antihyperlipidemic, antioxidant and hepatoprotective properties.     

5-(4-Hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates as potential hypolipidemic and hepatoprotective agents

Hypolipidemic effects of the newly synthesized 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates were evaluated in Triton WR-1339 and high-fat diet (HFD)-induced hyperlipidemic mice. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton WR-1339 model), in which compound 6 shown more significant antidyslipidemic activity than fenofibrate (FF). The compound 6 was also found to reduce serum triglyceride (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in HFD-induced hyperlipidemic mice. Moreover, compound 6 displayed hepatoprotective effect, a significant amelioration in hepatic indices (AST and ALT) toxicity was observed and the histological examination showed that compound 6 inhibited the development of hepatic lipid accumulation and ameliorated the damage in hepatic tissue compared to model mice. Additional effects such as the potent antioxidant and anti-inflammatory action confirmed and reinforced the efficacy of compound 6 as a new agent of dual-effect hypolipidemic and hepatoprotective activities.     

Effects of Korean white ginseng extracts on obesity in high-fat diet-induced obese mice

The present study examined the anti-obesity effect and mechanism of action of Korean white ginseng extracts (KGE) using high-fat diet (HFD)-induced obese mice. Mice were fed a low-fat diet (LFD), HFD or HFD containing 0.8 and 1.6% (w/w) KGE diet (HFD + 0.8KGE and HFD + 1.6KGE) for 8 weeks. We also examined the effects of KGE on plasma triglyceride (TG) elevation in mice administrated with oral lipid emulsion. Body weight gain and white adipose tissue (WAT) weight were significantly decreased in the HFD + 1.6KGE group, compared with the HFD group. The plasma TG levels were also significantly reduced in both HFD + 0.8KGE and HFD + 1.6KGE groups, while leptin levels were significantly decreased in only the HFD + 1.6KGE group, compared with the HFD group. The HFD + 1.6KGE group showed significantly lower mRNA levels of lipogenesis-related genes, including peroxisome proliferator-activated receptorγ2 (PPARγ2), sterol regulatory element binding protein-1c (SREBP-1c), lipoprotein lipase (LPL), fatty acid synthase (FAS) and diacylglycerol acyltransferase 1 (DGAT1), compared with the HFD group. In addition, a dose of 1000 mg/kg KGE inhibited the elevation of plasma TG levels compared with mice given the lipid emulsion alone. These results suggest that the anti-obesity effects of KGE may be elicited by regulating expression of lipogenesis-related genes in WAT and by delaying intestinal fat absorption.