Liver Sterol Research Articles

β-caryophyllene blocks reactive oxygen species-mediated hyperlipidemia in isoproterenol-induced myocardial infarcted rats

Myocardial infarction (MI) is a leading cause of death. Lipid-lowering interventions have been shown to decrease coronary events and mortality of MI and heart failure. In this investigation, we assessed the anti-hyperlipidemic effects of β-caryophyllene in isoproterenol-induced myocardial infarcted rats. β-Caryophyllene (20 mg/kg body weight) pre-and co-treatment was given to rats orally, daily, for 3 weeks. Isoproterenol (100 mg/kg body weight) was administered to rats to induce MI. The levels of serum cardiac troponins T and I, serum and heart total cholesterol, triglycerides, free fatty acids, and the levels of serum low-density and very low-density lipoprotein-cholesterols were augmented, and the level of serum high-density lipoprotein-cholesterol was lessened in myocardial infarcted rats. Further, the activity/levels of liver 3-hydroxy-3-methylglutaryl-coenzyme A reductase and plasma thiobarbituric acid reactive substances were amplified and the activity/levels of heart glutathione –S- transferase, vitamin C, and vitamin E were lessened by isoproterenol. A down-regulated expression of liver sterol regulatory element-binding protein-2 and liver low-density lipoprotein-receptor genes was observed by a reverse transcription-polymerase chain reaction study. Moreover, histopathology of Sudan III staining revealed an accumulation of fats in the heart of isoproterenol-induced rats. Nevertheless, β-caryophyllene pre-and co-treatment blocked alterations in all the parameters examined in isoproterenol-induced rats and inhibited the risk of MI. Moreover, the in vitro study revealed the potent free radical scavenging and antioxidant effects of β-caryophyllene. β-Caryophyllene's antioxidant and anti-hyperlipidemic properties are the possible mechanisms for the observed protective effects in this investigation.

Sparassis latifolia Polysaccharide Attenuates Cholesterol in Rats Maintained on a High-Fat, High-Cholesterol Diet

Sparassis latifolia polysaccharide (SLP) has broad application prospects as a raw material of functional food. This study aimed to investigate the effects of SLP on liver cholesterol metabolism and its mechanism. Sprague–Dawley rats were fed a high-fat, high-cholesterol diet, and various assessments were conducted including hematoxylin and eosin staining, measurement of liver and metabolic indices, and antioxidant analysis. In addition, fluorescence quantitative reverse transcription-polymerase chain reaction was performed to analyze mRNA expression, and gas chromatography-mass spectrometry was employed for screening differential metabolites. The results demonstrated that SLP reduced the abnormal increase in the liver index caused by high fat and cholesterol and improved liver tissue morphology, metabolism level, and antioxidant-related enzyme activities. The polysaccharide regulated the liver sterol metabolism pathway, decreased the mRNA expression levels of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) and sterol O-acyltransferase 1 (SOAT1), upregulated the mRNA expression levels of cholesterol 7α hydroxylase (CYP7α-1) and ABCA1, and increased the contents of propionic acid and butyric acid in the liver. These findings indicated a novel pathway through which SLP prevented hepatic lipid deposition and ameliorated sterol metabolism via regulating the HMG-CoAR-CYP7α-1 axis.

Effects of magnesium picolinate, zinc picolinate, and selenomethionine co-supplementation on reproductive hormones, and glucose and lipid metabolism-related protein expressions in male rats fed a high-fat diet

This study aimed to examine the impacts of the magnesium picolinate (MgPic), zinc picolinate (ZnPic), and selenomethionine (SeMet) alone or as a combination on blood metabolites, oxidative enzymes, reproductive hormones, and glucose and lipid metabolism-related protein expressions in Wistar rats fed a high-fed diet (HFD). The rats were fed either a control, HFD, or HFD supplemented with a single (MgPic, ZnPic, SeMet) or two or three organic mineral combinations. Body weights, visceral fat, serum glucose, insulin, total cholesterol, triglycerides, leptin, malondialdehyde (MDA) concentrations as well as liver sterol regulatory element-binding protein-1c (SREBP-1c), liver X receptor alpha (LXRα), ATP citrate lyase (ACLY), fatty acid synthase (FAS), and nuclear factor kappa B (NF-κB) levels increased, while serum testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone-binding globulin (SHBG), and insulin-like growth factor (IGF-1) concentrations along with liver nuclear factor erythroid 2-related factor 2 (Nrf2) levels declined in HFD rats (P < 0.05). Supplementing each organic mineral, but particularly the combination of HFD + MgPic + ZnPic + SeMet reversed the responses with various degrees. None of the organic elements alone or as a combination of two exerted a prominent effect on parameters measured. Although not additive or synergistic, the combination of all organic minerals added to HFD (HFD + MgPic + ZnPic + SeMet) provided the greatest responses.

Chronological Appearance of Endocrine and Metabolic Dysfunctions Induced by an Unhealthy Diet in Rats.

Background and Objectives: The work was aimed to determine the chronological sequence of events triggered by a fructose-rich diet (FRD) (10% w/v in the drinking water) in normal rats. Material and Methods: Serum parameters, liver and islet markers of metabolism, inflammation and oxidative stress were determined weekly for 21 days. Results: At the end of the first week, rats fed with a FRD showed an early increase in circulating triglycerides, fat liver deposit, and enzymatic activity of liver glucokinase and glucose-6-phosphate dehydrogenase (G6P-DH). After two weeks of such a diet, liver glucose-6-phosphatase (G6Pase) activity and liver oxidative stress markers were significantly increased. Liver sterol regulatory element-binding protein 1c (SREBP1c) mRNA also increased in the second week while their target genes fatty acid synthase (FAS) and glycerol-3-phosphate dehydrogenase (GPAT) enhanced their expression at the third week. Liver and pancreatic inflammation markers also enhanced their gene expression in the last week of treatment. Whereas both control and FRD rats remained normoglycemic throughout the entire period of treatment, blood insulin levels were significantly higher in FRD animals at the third week, thereby evidencing an insulin-resistant state (higher HOMA-IR, HOMA-B and HIS indexes). Pancreatic islets isolated from rats fed with a FRD for 3 weeks also increased glucose-induced insulin secretion (8.3 and 16.7 mM). Conclusions: FRD induces asynchronous changes involving early hypertriglyceridemia together with intrahepatic lipid deposit and metabolic disturbances from week one, followed by enhanced liver oxidative stress, liver and pancreas inflammation, pancreatic β-cell dysfunction, and peripheral insulin-resistance registered at the third week. Knowledge of time-course adaptation mechanisms involved in our rat model could be helpful in developing appropriate strategies to prevent the progression from prediabetes to Type 2 diabetes (T2D) triggered by unhealthy diets.

Mentha cordifolia Leaf Extract Improves Hepatic Glucose and Lipid Metabolism in Obese Mice Fed with High-Fat Diet.

Mentha cordifolia (MC) is a popular herb used to flavor food in Thailand that exhibits several biological effects. The present study aimed to determine the role of MC in regulating glucose and lipid metabolism in mice fed a high-fat diet (HFD). ICR obese mice were fed an HFD (45 kcal% lard fat) for 12 weeks, with MC (100 and 200 mg/kg/d) treatment from Week 7. After treatment with MC for 6 weeks, mice showed significantly lower rates of hyperglycemia, hyperinsulinemia, hyperleptinemia, and hyperlipidemia, and increased amounts of serum adiponectin. Furthermore, in mice treated with MC, serum interleukin-6 and tumor necrosis factor alpha were significantly inhibited and liver histology results showed decreased lipid accumulation and liver triglyceride content vs. untreated mice. In addition, MC treatment was associated with smaller fat cells and lower gene expression of liver sterol regulatory element binding protein 1c, acetyl-CoA carboxylase, and fatty acid synthase. However, MC treatment was associated with higher carnitine palmitoyltransferase 1a gene expression and significantly higher rates of adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in liver, but lower levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. These results indicate MC regulates glucose and lipid metabolism in a HFD-induced obese mouse model, possibly via activation of AMPK signaling pathway.

Modulatory effect of dry orange (citrus sinensis) peel powder on bisphenol A-induced hepatic and splenic toxicity in rats

BackgroundBisphenol A (BPA) is used as monomer in polycarbonate synthesis, and it acts as plasticizer in baby and water bottles and the production of epoxy resins which are used as inner coatings of many food and beverage cans. This study was carried out to evaluate the possible modulatory effect of dry orange peels powder (OPP) to attenuate the toxic effects of BPA on liver and spleen in rats.MethodSixty male Spargue–Dawley rats weighing 130 ± 10 g were randomly divided into six groups (n = 10 for each group). Group 1: negative control, fed on balanced diet and received corn oil. Group 2: positive control, fed on balanced diet, received BPA (350 mg/kg b.w. per orally; p.o twice weekly) suspended in corn oil. Groups from 3 to 6 fed on balanced diet supplemented with OPP in the tested doses of 12.5, 25, 50, and 100 g/Kg diet respectively, and received BPA (350 mg/kg b.w. twice weekly).ResultsThere was a significant increase in liver sterol regulatory element-binding transcription factor 1 gene expression (SREBF1), serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, nitric oxide (NO), total cholesterol (TC), triacylglycerols (TAGs), low-density lipoprotein cholesterol (LDL-c), very low-density lipoprotein cholesterol (VLDL-c), interluken-4 (IL-4), immunoglobulin-E (IgE)levels, and total leukocytes count (TLC) in BPA group as compared to negative control group (P < 0.05).On the other hand, BPA caused a significant decrease in liver catalase activity, serum high-density lipoprotein cholesterol (HDL-c), serum immunoglobulin-M (IgM) levels, blood hemoglobin% (Hb), and red blood cell (RBCs) counts compared to the negative control group (P < 0.05). Also, the histopathological examination of liver and spleen sections supported biochemical parameters showed a significant destruction in the BPA group as compared to the negative control group.ConclusionIt is observed that OPP dietary supplementation in the tested doses ameliorates deleterious effects induced by BPA. The improvement in these altered parameters in OPP supplemented groups was in a dose-dependent manner.

Cholesterol-reducing effect of ergosterol is modulated via inhibition of cholesterol absorption and promotion of cholesterol excretion

Abstract Ergosterol is the common sterol found in edible mushrooms. This study investigated the cholesterol-reducing effect of ergosterol and its related potential mechanism in Sprague-Dawley rats. Thirty-two male rats were divided into four groups fed either a basic diet (NG) or one of three experimental diets, namely high-cholesterol diet (HC), and the two HC diets containing 0.5% ergosterol (EL) and 1.5% ergosterol (EH), respectively, for 8 weeks. Results demonstrated that feeding EL and EH diets decreased serum total cholesterol (TC) by 19.4–21.6%, low density lipoproptein cholesterol (LDL-C) by 42.0–42.6%, and TC/HDL-C ratio by 7.1–10.5%. This was accompanied by 46.8–53.2% reduction in liver cholesterol and 51.0–59.3% increase in fecal cholesterol excretion with up-regulation on gene expression of liver sterol regulatory element-binding protein 2 (SREBP-2), low-density lipoprotein receptor (LDL-R) and Hydroxy-3-Methylglutaryl-Coenzyme A Reductase (HMG-CoR). Results from micelles formation assay in vitro clearly demonstrated that ergosterol could significantly inhibit the entry of cholesterol into micelles. Therefore, the cholesterol-reducing effect of ergosterol was regulated by suppressing intestine cholesterol absorption and promoting the excretion of fecal cholesterol via modulating the expression of hepatic cholesterol-related genes.

Anti-Obesity Effect of Chitosan Oligosaccharide Capsules (COSCs) in Obese Rats by Ameliorating Leptin Resistance and Adipogenesis.

Obesity is a global disease that causes many metabolic disorders. However, effective agents for the prevention or treatment of obesity remain limited. This study investigated the anti-obesity effect and mechanism of chitosan oligosaccharide capsules (COSCs) on rats suffering from obesity induced by a high-fat diet (HFD). After the eight-week administration of COSCs on obese rats, the body weight gain, fat/body ratio, and related biochemical indices were measured. The hepatic expressions of the leptin signal pathway (JAK2-STAT3) and gene expressions of adipogenesis-related targets were also determined. Our data showed that COSCs can regulate body weight gain, lipids, serum alanine aminotransferase, and aspartate aminotransferase, as well as upregulate the hepatic leptin receptor-b (LepRb) and the phosphorylation of JAK2 and STAT3. Meanwhile, marked increased expressions of liver sterol regulatory element-binding protein-1c, fatty acid synthase, acetyl-CoA carboxylase, 3-hydroxy-3-methylglutaryl-CoA reductase, adiponectin, adipose peroxisome proliferator-activated receptor γ, CCAAT-enhancer binding protein α, adipose differentiation-related protein, and SREBP-1c were observed. The results suggested that COSCs activate the JAK2-STAT3 signaling pathway to alleviate leptin resistance and suppress adipogenesis to reduce lipid accumulation. Thus, they can potentially be used for obesity treatment.

Crystal structure of the human sterol transporter ABCG5/ABCG8.

ATP binding cassette (ABC) transporters play critical roles in maintaining sterol balance in higher eukaryotes. The ABCG5/ABCG8 heterodimer (G5G8) mediates excretion of neutral sterols in liver and intestines. Mutations disrupting G5G8 cause sitosterolaemia, a disorder characterized by sterol accumulation and premature atherosclerosis. Here we use crystallization in lipid bilayers to determine the X-ray structure of human G5G8 in a nucleotide-free state at 3.9 Å resolution, generating the first atomic model of an ABC sterol transporter. The structure reveals a new transmembrane fold that is present in a large and functionally diverse superfamily of ABC transporters. The transmembrane domains are coupled to the nucleotide-binding sites by networks of interactions that differ between the active and inactive ATPases, reflecting the catalytic asymmetry of the transporter. The G5G8 structure provides a mechanistic framework for understanding sterol transport and the disruptive effects of mutations causing sitosterolaemia.

Blood Lipid Components and SREBP-1 Gene Expression in Broiler Chickens Fed Different Dietary Lipid Sources

Background: Liver plays an important role in energy homeostasis. Intense liver diseases are accompanied with lower concentrations of n-3 and n-6 poly unsaturated fatty acids (PUFA). It has been found that n-3 PUFA play importantly protective roles in the liver. There was limited information about the effects of lipid sources on serum lipid components and liver sterol regulatory element binding-1 (SREBP-1) gene expression. Therefore, the aim of this study was to evaluate and compare the effects of fish oil, corn oil, olive oil and tallow, respectively, as dietary sources of n-3, n-6, n-9 and saturated fatty acid on serum lipid compound and liver SREBP-1 gene expression in broiler chicks.Materials, Methods &amp; Results: In a completely randomized design, 240 one-day-old broiler chicks were allocated to five dietary treatments, four replicates and 12 chicks per each. Dietary treatments included of: control (diet without lipid supplementation) and diet supplemented with fish oil as a n-3 fatty acid source, corn oil as a n-6 fatty acid source, olive oil as a n-9 fatty acid source and tallow as a saturated fatty acid which were added to diets at 1.5, 3 and 4% in the starter, grower and finisher, respectively. At days 28 and 42 of age, liver tissue was dissected out and samples were placed in liquid nitrogen, also blood samples were collected. The SREBP-1 mRNA expression in liver tissue was quantitated using RT-PCR. Broilers fed diets containing fish oil, corn oil and olive oil as unsaturated fatty acid sources had lower concentrations of triacylglycerol than those fed other diets. Also, diets containing fish oil and tallow showed the lowest low density lipoprotein (LDL) levels at day 28 of age. Diets containing corn oil and olive oil showed higher levels of cholesterol and high density lipoprotein (HDL) than other diets but, these differences were not significant at days 28 and 42 of age (P ≥ 0.05). In both sampling periods, the chickens fed diets containing tallow expressed higher (P &lt; 0.05) SREBP-1 gene as compared to those fed other dietary lipids. Broilers fed diet containing corn oil had higher (P &lt; 0.05) SREBP-1 gene expression than those fed diet containing fish oil and olive oil.Discussion: Serum lipids were affected by dietary fat source. Lower concentration of serum triacylglycerols was found in broilers fed fish oil and corn oil diets as dietary n-3 and n-6 fatty acid sources. It was shown that dietary PUFA, especially n-6 and n-3 fatty acids could reduce hepatic fatty acid and triacylglycerol synthesis. Broilers fed corn oil diet showed elevated LDL levels respect with those fed fish oil or tallow at day 28 of age. The results showed that dietary polyunsaturated fatty acids and saturated fatty acids substantially affected on SREBP-1 gene expression at days 28 and 42 of age. The birds fed fish oil as n-3 PUFA source expressed lower SREBP-1 gene compared with other groups at day 28 of age. Longer chain length, high number of double bonds, and the presence of the first double bond gives these fatty acids distinct and unique properties that separate them and their metabolic products from the more common n-6 and n-9 fatty acids. The finding of this study indicated lipogenic effects of tallow and then corn oil. The results confirmed that each of dietary lipid sources had different effect on serum lipid components. It was also found that SREBP-1 gene expression is age-dependent and it increased as age of broilers increased.

Plasma triacylglycerol‐lowering activity of citrus polymethoxylated flavones is mediated by modulating the genes involved in lipid metabolism in hamsters

The present study investigated the underlying mechanism by which citrus polymethoxylated flavones (PMF) reduced plasma triacylglycerols (TG) in hamsters. Four groups of male hamsters were given a non‐cholesterol diet (NCD), a high cholesterol diet (HCD), a high cholesterol diet with supplementation of 0.5% PMF (L‐PMF), and a high cholesterol diet with supplementation of 1.0% PMF (H‐PMF), respectively, for 8 weeks. Results showed PMF could lower plasma TG by 32–46%, but it had no effect on plasma cholesterol. This was accompanied by down‐regulation of mRNA of liver sterol regulatory element binding protein‐1c (SREBP1c), fatty acid synthase (FAS), and peroxisome proliferator activated receptor alpha (PPARα) while up‐regulation of liver lipoprotein lipase (LPL). In addition, dietary PMF increased cholesterol by 5–15% and total lipids by 34–43% in the liver. PMF supplementation also reduced the body weight gain and the relative weights of white adipose tissue pads by 23–39%, possibly by decreasing the gene expression of FAS and LPL in the epididymal fat pad. It was concluded that plasma TG‐lowering activity of dietary PMF was mediated by modulating genes involved in lipid metabolism in hamsters.Practical applications: Hyperlipidemia is one of the risk factors for coronary heart diseases. The present study found that polymethoxylated flavones (PMF) were effective in reducing plasma triacylglycerols and adipose tissue weight. PMF may be developed as a nutraceutical to prevent hyperlipidemia and obesity.Citrus polymethoxylated flavones are able to reduce plasma triacylglycerols via two mechanisms of inhibition of lipogenesis and enhancement of lipid uptake by the liver, most likely mediated by down‐regulation of SREBP1c and FAS along with up‐regulation of LPL in the liver.

Effects of cholesterol-supplemented and unsupplemented diets containing unextracted and extracted Syzygium cumini seeds on lipid profiles of alloxan-induced diabetic albino rats

Background: Hypercholesterolemia and hyperlipidemia are the major problems associated with diabetes. Various agents are being tried to solve these so that problems related to micro- and macroangiopathy can be averted. Plant fibers particularly water-soluble gummy fibers have been reported earlier to reduce blood lipids and cholesterol levels in normal and diabetic animals and humans. Objective: Effects of cholesterol-supplemented and unsupplemented diets containing unextracted and extracted Syzygium cumini seeds on lipid profiles of alloxan-induced diabetic albino rats Material and Methods: Powder of Syzygium cumini seeds was successively extracted using organic solvents, and hypolipidemic and hypocholesterolemic activities of 15% unextracted, 15% extracted, and 15% degummed S. cumini seeds with cholesterol-supplemented and unsupplemented diets were assayed in normal and alloxan-induced diabetic rats. Result: In this study, significant decrease in the levels of total serum cholesterol, serum triglycerides, serum phospholipids, and total cholesterol and triglycerides in tissues of liver, heart, and aorta was observed. Also, significant increase was observed in the phospholipid levels in tissues of liver, heart, aorta, and biliary, and fecal bile acid content and sterols in normal and alloxan-induced diabetic rats. Conclusion: The hypocholesterolemic and hypolipidemic effects of S. cumini seeds may be attributed to their watersoluble gel-forming gummy fiber acting by decreasing cholesterol absorption and breakdown leading to an increased fecal excretion of bile acids and sterols.

Dietary strawberry seed oil affects metabolite formation in the distal intestine and ameliorates lipid metabolism in rats fed an obesogenic diet

ObjectiveTo answer the question whether dietary strawberry seed oil rich in α-linolenic acid and linoleic acid (29.3 and 47.2% of total fatty acids, respectively) can beneficially affect disorders induced by the consumption of an obesogenic diet.DesignThirty-two male Wistar rats were randomly assigned to four groups of eight animals each and fed with a basal or obesogenic (high in fat and low in fiber) diet that contained either strawberry seed oil or an edible rapeseed oil. A two-way analysis of variance was then applied to assess the effects of diet and oil and the interaction between them.ResultsAfter 8 weeks of feeding, the obesogenic diet increased the body weight and the liver mass and fat content, whereas decreased the cecal acetate and butyrate concentration. This diet also altered the plasma lipid profile and decreased the liver sterol regulatory element-binding protein 1c (SREBP-1c) content. However, the lowest liver SREBP-1c content was observed in rats fed an obesogenic diet containing strawberry seed oil. Moreover, dietary strawberry seed oil decreased the cecal short-chain fatty acid concentrations (acetate, propionate, and butyrate) regardless of the diet type, whereas the cecal β-glucuronidase activity was considerably increased only in rats fed an obesogenic diet containing strawberry seed oil. Dietary strawberry seed oil also lowered the liver fat content, the plasma triglyceride level and the atherogenic index of plasma.ConclusionsStrawberry seed oil has a potent lipid-lowering activity but can unfavorably affect microbial metabolism in the distal intestine. The observed effects are partly due to the synergistic action of the oil and the obesogenic diet.

Pharmacologic profile of the Adnectin BMS-962476, a small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering.

Proprotein convertase subtilisin kexin-9 (PCSK9) is an important pharmacological target for decreasing low-density lipoprotein (LDL) in cardiovascular disease, although seemingly inaccessible to small molecule approaches. Compared with therapeutic IgG antibodies currently in development, targeting circulating PCSK9 with smaller molecular scaffolds could offer different profiles and reduced dose burdens. This inspired genesis of PCSK9-binding Adnectins, a protein family derived from human fibronectin-10th-type III-domain and engineered for high-affinity target binding. BMS-962476, an ∼11-kDa polypeptide conjugated to polyethylene glycol to enhance pharmacokinetics, binds with subnanomolar affinity to human. The X-ray cocrystal structure of PCSK9 with a progenitor Adnectin shows ∼910 Å(2) of PCSK9 surface covered next to the LDL receptor binding site, largely by residues of a single loop of the Adnectin. In hypercholesterolemic, overexpressing human PCSK9 transgenic mice, BMS-962476 rapidly lowered cholesterol and free PCSK9 levels. In genomic transgenic mice, BMS-962476 potently reduced free human PCSK9 (ED50 ∼0.01 mg/kg) followed by ∼2-fold increases in total PCSK9 before return to baseline. Treatment of cynomolgus monkeys with BMS-962476 rapidly suppressed free PCSK9 >99% and LDL-cholesterol ∼55% with subsequent 6-fold increase in total PCSK9, suggesting reduced clearance of circulating complex. Liver sterol response genes were consequently downregulated, following which LDL and total PCSK9 returned to baseline. These studies highlight the rapid dynamics of PCSK9 control over LDL and liver cholesterol metabolism and characterize BMS-962476 as a potent and efficacious PCSK9 inhibitor.

High density lipoproteins improve insulin sensitivity in high-fat diet-fed mice by suppressing hepatic inflammation

Obesity-induced liver inflammation can drive insulin resistance. HDL has anti-inflammatory properties, so we hypothesized that low levels of HDL would perpetuate inflammatory responses in the liver and that HDL treatment would suppress liver inflammation and insulin resistance. The aim of this study was to investigate the effects of lipid-free apoAI on hepatic inflammation and insulin resistance in mice. We also investigated apoAI as a component of reconstituted HDLs (rHDLs) in hepatocytes to confirm results we observed in vivo. To test our hypothesis, C57BL/6 mice were fed a high-fat diet (HFD) for 16 weeks and administered either saline or lipid-free apoAI. Injections of lipid-free apoAI twice a week for 2 or 4 weeks with lipid-free apoAI resulted in: i) improved insulin sensitivity associated with decreased systemic and hepatic inflammation; ii) suppression of hepatic mRNA expression for key transcriptional regulators of lipogenic gene expression; and iii) suppression of nuclear factor κB (NF-κB) activation. Human hepatoma HuH-7 cells exposed to rHDLs showed suppressed TNFα-induced NF-κB activation, correlating with decreased NF-κB target gene expression. We conclude that apoAI suppresses liver inflammation in HFD mice and improves insulin resistance via a mechanism that involves a downregulation of NF-κB activation.

Hormonal modulators of glial ABCA1 and apoE levels

Apolipoprotein E (apoE) is the major lipid carrier in the central nervous system. As apoE plays a major role in the pathogenesis of Alzheimer disease (AD) and also mediates repair pathways after several forms of acute brain injury, modulating the expression, secretion, or function of apoE may provide potential therapeutic approaches for several neurological disorders. Here we show that progesterone and a synthetic progestin, lynestrenol, significantly induce apoE secretion from human CCF-STTG1 astrocytoma cells, whereas estrogens and the progesterone metabolite allopregnanolone have negligible effects. Intriguingly, lynestrenol also increases expression of the cholesterol transporter ABCA1 in CCF-STTG1 astrocytoma cells, primary murine glia, and immortalized murine astrocytes that express human apoE3. The progesterone receptor inhibitor RU486 attenuates the effect of progestins on apoE expression in CCF-STTG1 astrocytoma cells but has no effect on ABCA1 expression in all glial cell models tested, suggesting that the progesterone receptor (PR) may participate in apoE but does not affect ABCA1 regulation. These results suggest that selective reproductive steroid hormones have the potential to influence glial lipid homeostasis through liver X receptor-dependent and progesterone receptor-dependent pathways.

A low-protein, high-carbohydrate diet increases de novo fatty acid synthesis from glycerol and glycerokinase content in the liver of growing rats

We had previously shown that adipose tissue increased in rats fed a low-protein, high-carbohydrate (LPHC) diet (6% protein, 74% carbohydrate) without a simultaneous increase in the de novo fatty acids (FA) synthesis. In addition, impairment in insulin signaling in adipose tissues was observed in these rats. For this study, we hypothesized that the insulin signaling pathway is preserved in the livers from these rats, which contributes to an increase in liver lipogenesis and, consequently, an increase in the weight of the adipose tissue. We also hypothesized that glycerol from triacylglycerol is an important substrate for FA synthesis. Our results showed that administration of the LPHC diet induced an increase in the in vivo rate of total FA synthesis (150%) as well as FA synthesis from glucose (270%) in the liver. There were also increased rates of [U-14C]glycerol incorporation into glyceride-FA (15-fold), accompanied by increased glycerokinase content (30%) compared with livers of rats fed the control diet. The LPHC diet did not change the glycerol-3-phosphate generation from either glucose or glyceroneogenesis. There was an increase in the insulin sensitivity in liver from LPHC-fed rats, as evidenced by increases in IRβ (35%) levels and serine/threonine protein kinase (AKT) levels (75%), and basal (95%) and insulin-stimulated AKT phosphorylation (105%) levels. The LPHC diet also induced an increase in the liver sterol regulatory element-binding protein–1c content (50%). In summary, these data confirmed the hypothesis that lipogenesis and insulin signaling are increased in the livers of LPHC-fed rats and that glycerol is important not only for FA esterification but also for FA synthesis.

The effects of phytosterol supplementation on serum LDL-C levels and learning ability in mice fed a high-fat, high-energy diet from gestation onward

A high-fat, high-energy (HFE) diet may be deleterious to the cardiovascular system and mental health. We previously reported that serum cholesterol levels and escape latency were significantly increased in mice by feeding them an HFE diet from gestation onward. In this study, we examined whether an HFE diet supplemented with phytosterols fed to pregnant C57BL/6j dams and their offspring would protect the HFE-diet-induced compromise of the offspring’s learning capability. We measured serum cholesterol levels, brain N-methyl-D-aspartate receptor (NMDAR1) mRNA and protein expression and liver sterol 27-hydroxylase (Cyp27a1) mRNA expression, as well as a Morris water maze performance. The results showed that, compared to mice consuming the HFE diet alone, those also consuming phytosterols (the HFE + PS diet) significantly decreased mean serum low-density lipoprotein cholesterol levels and altered brain NMDAR1 mRNA and protein expression and liver Cyp27a1 mRNA expression. The Morris water maze experiments indicated that dietary phytosterol supplementation slightly decreased the escape latency (p = 0.07). Collectively, these observations suggest that consumption of phytosterols from early in life may help alleviate the detrimental effects of HFE diets in mice.

Combination effect of phospholipids and n-3 polyunsaturated fatty acids on rat cholesterol metabolism

This study evaluated phospholipids (PLs) containing n-3 polyunsaturated fatty acids (n-3 PUFAs) for their specific inherent effects and effects due to a combination of the presence of glycerophosphate structure and n-3 PUFAs on cholesterol metabolism in rats. Rats were fed a diet of AIN-93G containing soybean oil (SO, 7%), SO (5.8%)+fish oil (1.2%), SO (5.2%)+soybean PLs (1.8%), SO (5.2%)+PLs containing n-3 PUFAs (1.8%), and SO (4.0%)+fish oil (1.2%)+soybean PLs (1.8%). Diets with PLs containing n-3 PUFAs, and soybean PLs in combination with fish oil, resulted in decreased serum and liver cholesterol levels through enhancement of fecal cholesterol excretion and suppression of liver sterol regulatory element binding protein-2 mRNA expression compared with the diet containing soybean oil alone. This study shows that soybean PLs with added triacylglycerol that included n-3 PUFAs have the same effects on cholesterol metabolism as PLs containing n-3 PUFAs, and that these could be of benefit to people.

Reduced biliary sterol output with no change in total faecal excretion in mice expressing a human apolipoprotein A‐I variant

Apolipoprotein (apo)A-I(M) (ilano), is a molecular variant of apoA-I(wild-type), associated with dramatically low HDL-cholesterol levels, but no increased risk for cardiovascular disease. In view of the present uncertainties on the role of apoA-I in liver cholesterol removal by way of bile acids and neutral sterols, and of the greater capacity of apoA-I(M) (ilano) to remove arterial cholesterol, biliary sterol metabolism was evaluated in transgenic mice expressing apoA-I(M) (ilano). ApoA-I(M) (ilano) mice were fed a high-cholesterol/high-fat diet, and compared with human apoA-I(wild-type) mice. Plasma lipid levels, hepatic bile flow and composition, hepatic and intestinal cholesterol and bile acid content, and faecal sterol content were measured. Moreover, the expression of hepatic ABCA1, SR-B1 and that of hepatic and intestinal genes involved in bile acid metabolism were evaluated. The dietary treatment led to a strong elevation in HDL-cholesterol levels in A-I(M) (ilano) mice, associated with an increased expression of hepatic ABCA1. ApoA-I(M) (ilano) mice showed lower cholesterol output from the liver compared with apoA-I(wild-type) mice, in the absence of liver sterol accumulation. Faecal excretion of neutral sterols and bile acids was similar in the two mouse lines. In spite of a different response to the dietary challenge, with an increased ABCA1 expression and a lower hepatic cholesterol output in apoA-I(M) (ilano) mice, the net sterol excretion is comparable in the two transgenic lines.