Increased Cholesterol Excretion Research Articles

Intestinal epithelial cell NCoR deficiency ameliorates obesity and metabolic syndrome

Nuclear receptor corepressor (NCoR1) interacts with various nuclear receptors and regulates the anabolism and catabolism of lipids. An imbalance in lipid/energy homeostasis is also an important factor in obesity and metabolic syndrome development. In this study, we found that the deletion of NCoR1 in intestinal epithelial cells (IECs) mainly activated the nuclear receptor PPARα and attenuated metabolic syndrome by stimulating thermogenesis. The increase in brown adipose tissue thermogenesis was mediated by gut-derived tricarboxylic acid cycle intermediate succinate, whose production was significantly enhanced by PPARα activation in the fed state. Additionally, NCoR1 deletion derepressed intestinal LXR, increased cholesterol excretion, and impaired duodenal lipid absorption by decreasing bile acid hydrophobicity, thereby reversing the possible negative effects of intestinal PPARα activation. Therefore, the simultaneous regulatory effect of intestinal NCoR1 on both lipid intake and energy expenditure strongly suggests that it is a promising target for developing metabolic syndrome treatment.

KAJIANPUSTAKA: HIPERKOLESTEROLEMIADAN PENANGGULANGANNYA DENGAN MENGGUNAKANBERBAGAI SENYAWA BIOAKTIF

Hypercholesterolemia is characterized by levels of total cholesterol and low-density lipoprotein (LDL) above normal. Hypercholesterolemia is a major risk factor for cardiovascular disease. This study was aimed to explore and analyze various bioactive compounds to manage hypercholesterolemia. Efforts to overcome the condition of hypercholesterolemia are to reduce the consumption of a diet rich in cholesterol and calories, and consuming contemporary hypercholesterolemic drugs such as statins, as well as by regulating the body’s cholesterol metabolism with various antihypercholesterolemic bioactive compounds. Various findings of antihypercholesterolemic bioactive compounds have various sources and effects on cholesterol profiles. Bioactive compounds can be classified according to their mechanism of hypocholesterolemic action, which are inhibition of cholesterol absorption, inhibition of cholesterol biosynthesis, increased cholesterol excretion, increased cholesterol reverse transport, and increased cholesterol catabolism. Several bioactive compounds are involved in a dual mechanism. The development of these various bioactive compounds can be used as an alternative treatment for hypercholesterolemia since contemporary medicines have proven to have many side effects.

Red kidney bean (Phaseolus vulgaris L.) instant porridge: Effect of isomaltooligosaccharides and Fibercreme as sucrose replacement on lipid profile improvement in hypercholesterol-induced rats

The aim of the present study was to evaluate the effect of consumption pregelatinized kidney bean porridge with variation of sweetener including sucrose (BKM S), isomaltooligosaccharides (BKM IMO) and Fibercreme (BKM FC) in hypercholesterolemia rats on the lipid profile, bile acid binding capacity, digesta cholesterol excretion and digesta characters including weight, water content and pH. The diets included standard diet for Negative Control rats (NC diet) and kidney bean porridge diets with different sweeteners: sucrose (BKM S diet), IMO (BKM IMO diet) and fibercreme (BKM FC diet), respectively. Red kidney bean instant porridge substituted 30% of total calories of the diets. All of the diets were formulated based on AIN 93M standard and were fed for 28 days. The result showed that BKM IMO and BKM FC diets improve lipid profile of rats by reducing total cholesterol, LDL cholesterol and triglycerides and increasing HDL cholesterol. In addition, both diets increased cholesterol excretion. In vitro measurement of bile acid binding capacity showed that BKM IMO and BKM FC have a higher binding capacity than BKM S. It can be argued that increasing of cholesterol excretion and bile acids binding capacity of these diets are responsible for the improving of the lipid profile. BKM IMO and BKM FC have higher digesta weight and water content but lower pH. It is concluded that substitution of sucrose as sweetener with isomalto-oligosaccharides and Fibercreme in the formulation of pregelatinized kidney bean porridge improve the beneficial health effect of kidney bean porridge.

The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis.

Cardiovascular diseases, especially atherosclerosis and its complications, are a leading cause of death. Inhibition of the noncanonical IκB kinases TANK-binding kinase 1 and IKKε with amlexanox restores insulin sensitivity and glucose homeostasis in diabetic mice and human patients. Here we report that amlexanox improves diet-induced hypertriglyceridemia and hypercholesterolemia in Western diet–fed (WD-fed) Ldlr–/– mice and protects against atherogenesis. Amlexanox ameliorated dyslipidemia, inflammation, and vascular dysfunction through synergistic actions that involve upregulation of bile acid synthesis to increase cholesterol excretion. Transcriptomic profiling demonstrated an elevated expression of key bile acid synthesis genes. Furthermore, we found that amlexanox attenuated monocytosis, eosinophilia, and vascular dysfunction during WD-induced atherosclerosis. These findings demonstrate the potential of amlexanox as a therapy for hypercholesterolemia and atherosclerosis.

ACUTE PANCREATITIS AND PREGNANCY : A RARE AND SEVERE ASSOCIATION

Introduction Acute pancreatitis associated with pregnancy is a serious condition, surgical discovery or even necropsy and difficult diagnosis. We report a case of acute pancreatitis occurring in a pregnant woman. Observation This is a 29-year-old woman, nulliparous with no previous pathological history, presented to obstetric emergencies for hepatic colic. The patient had no transit disorder or gastrointestinal bleeding. Clinically, the patient was feverish, blood pressure was 16/9 mmHg and her hemodynamic status was stable. Obstetrical examination was normal, correlated with gestational age. The biological assessment performed showed anemia. The viral serology performed was negative. Liver status, renal status and coagulation status were normal. The diagnosis was acute pancreatitis and pre-eclampsia in pregnancy. Discussion Acute pancreatitis rarely occurs during pregnancy. It is associated with high maternal and fetal mortality. It occurs in most cases in the 3rd trimester of pregnancy [1]. In the 2nd and 3rd trimesters, supersaturation of bile in relation to increased cholesterol excretion and stagnation of supersaturated bile in the gallbladder induces formation of cholesterol crystals and gallstones [2]. In the 3rd trimester, the gravid uterus compresses the common bile duct and can lead to acute pancreatitis. Acute pancreatitis during pregnancy may be associated with pre-eclampsia that increases fetal mortality [3]. Conclusion Acute pancreatitis during pregnancy is a rare association, difficult to diagnose and has a terrible prognosis for both the mother and the fetus. The diagnostic and therapeutic delay will be fatal to the mother-child couple.

Anti-atherosclerotic effects of an improved apolipoprotein A-I mimetic peptide

BackgroundApolipoprotein (Apo)A-I is a major protein component of high-density lipoprotein (HDL) that causes cholesterol efflux from peripheral cells through ATP-binding cassette transporter A1 (ABCA1) and the generation of HDL. Furthermore, it has a possible protective function against atherosclerotic cardiovascular disease (ASCVD). We previously developed a novel ApoA-I mimetic peptide without phospholipids (Fukuoka University ApoA-I Mimetic Peptide, FAMP). According to our previous studies, FAMP had an anti-arteriosclerotic effect. Since the required dose and reaction time of conventional FAMP were relatively large and short, respectively, we newly developed an improved FAMP (i-FAMP). Methods and resultsWe synthesized four candidate i-FAMPs, i-FAMP-D1, -D2, -D3 and -D4, and examined which i-FAMP has greater cholesterol efflux capacity than FAMP in A172 human glioblastoma cells transiently transfected with human ABCA1 cDNA. Only i-FAMP-D1 showed significantly greater cholesterol efflux capacity than conventional FAMP. i-FAMP-D1 formed stronger α-helical conformations than FAMP as assessed by circular dichroism spectra. Thus, we selected i-FAMP-D1 for further experiments. i-FAMP-D1 had a greater atheroprotective effect than FAMP in ApoE knockout mice. In addition, i-FAMP-D1 activated cholesterol efflux from macrophage to HDL more strongly than FAMP and increased cholesterol excretion from liver to feces. ConclusionThese results suggest that i-FAMP-D1 has a stronger anti-atherosclerotic effect than conventional FAMP.

Fucoidan A2 from the Brown Seaweed Ascophyllum nodosum Lowers Lipid by Improving Reverse Cholesterol Transport in C57BL/6J Mice Fed a High-Fat Diet.

Reverse cholesterol transport (RCT) is a physiological process, in which excess peripheral cholesterol is transported to the liver and further excreted into the bile and then feces. Recently, fucoidans are reported to have a lipid-lowering effect. This study was designed to investigate whether fucoidan from the brown seaweed Ascophyllum nodosum lowers lipid by modulating RCT in C57BL/6J mice fed a high-fat diet. Our results indicated that fucoidan intervention significantly reduced plasma triglyceride, total cholesterol, and fat pad index and markedly increased high-density lipoprotein cholesterol in a dose-dependent manner. In the liver, fucoidan significantly increased the expression of peroxisome proliferator-activated receptor (PPAR)α, PPARγ, liver X receptor (LXR)β, adenosine triphosphate (ATP) binding cassette (ABC)A1, ABCG8, low-density lipoprotein receptor (LDLR), scavenger receptor B type 1 (SR-B1), and cholesterol 7-α-hydroxylase A1 (CYP7A1) and decreased the triglyceride level and expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) and PPARβ but had no effect on LXRα, ABCG1, and ABCG5. In the small intestine, the fucoidan treatment significantly reduced the expression of Niemann-Pick C1-like 1 (NPC1L1) and improved ABCG5 and ABCG8. These results demonstrated that fucoidan can improve lipid transfer from plasma to the liver by activating SR-B1 and LDLR and inactivating PCSK9 and upregulate lipid metabolism by activating PPARα, LXRβ, ABC transporters, and CYP7A1. In the small intestine, this fucoidan can decrease cholesterol absorption and increase cholesterol excretion by activating NPC1L1 and ABCG5 and ABCG8, respectively. In conclusion, fucoidan from A. nodosum may lower lipids by modulating RCT-related protein expression and can be explored as a potential compound for prevention or treatment of hyperlipidemia-related diseases.

Milk fermented with probiotic strains Lactobacillus rhamnosus MTCC: 5957 and Lactobacillus rhamnosus MTCC: 5897 ameliorates the diet-induced hypercholesterolemia in rats

The current study was intended to investigate the cholesterol-lowering potential of the two Lactobacillus rhamnosus probiotic strains, LR 5957 and LR 5897, isolated from ‘dahi’. Cholesterol-lowering ability of both strains was determined in in vitro conditions. For in vivo investigations, the Wistar rats were randomly assigned into five groups and treated with different diets: standard diet (SD), high-cholesterol diet (HCD), HCD with Milk, HCD with LR 5957–fermented milk, and HCD with LR 5897–fermented milk. After 3 months of feeding, different parameters of hypercholesterolemia were measured in blood, feces, liver, and kidney. Both the strains, LR 5957 and LR 5897, showed the ability to grow in the presence of cholesterol and eliminate the cholesterol under in vitro conditions. In vivo results indicate that consumption of probiotic-fermented milk has significantly reduced the HCD-induced body weight, hyperlipidemia, and hepatic lipids (total cholesterol and triacylglycerol). Further, increased cholesterol excretion in feces was also observed in probiotic-fed groups. The studied fermented milk also helped to maintain healthy liver and kidney by increasing the antioxidant activities and decreasing the lipid peroxidation. Consumption of probiotic-fermented milk also found to decrease the mRNA expression of the inflammatory markers TNF-α and IL-6 in the liver. Overall, our results indicate that the L. rhamnosus strains, LR 5957 and LR 5897, are two potential probiotic strains that can ameliorate the diet-induced hypercholesterolemia.

The TICE Pathway: Mechanisms and Lipid-Lowering Therapies.

Besides the well-known hepatobiliary pathway of cholesterol excretion into the feces, transintestinal cholesterol excretion (TICE) is a second major pathway through which cholesterol is disposed from the body. In the process of TICE, cholesterol is taken up from lipoprotein particles at the basolateral side of the enterocyte and translocates towards the apical side of the enterocyte. At the apical side, the ATP-binding cassette transporters G5 and G8 form a heterodimer that transports cholesterol into the intestinal lumen. A substantial amount of the secreted cholesterol is likely reabsorbed by the cholesterol influx transporter Niemann-Pick C1-Like 1 (NPC1L1) since recent data indicate that inhibition of NPC1L1 increases the efficacy of TICE for disposal of cholesterol via the feces. The pathways and proteins involved in intracellular cholesterol trafficking in the enterocyte have not yet been identified. Therefore, in addition to discussing known mediators of TICE, this review will also examine potential candidates involved in cholesterol translocation in the enterocyte. Both the cholesterol reuptake and efflux pathways can be influenced by pharmaceutical means; thus, the TICE pathway is a very attractive target to increase cholesterol excretion from the body and prevent or mitigate atherosclerotic cardiovascular disease.

Low-Density Lipoprotein-Reactive T Cells Regulate Plasma Cholesterol Levels and Development of Atherosclerosis in Humanized Hypercholesterolemic Mice

Atherosclerotic cardiovascular disease is a chronic inflammatory process initiated when cholesterol-carrying low-density lipoprotein (LDL) is retained in the arterial wall. CD4+ T cells, some of which recognize peptide components of LDL as antigen, are recruited to the forming lesion, resulting in T-cell activation. Although these T cells are thought to be proatherogenic, LDL immunization reduces disease in experimental animals. These seemingly contradictory findings have hampered the development of immune-based cardiovascular therapy. The present study was designed to clarify how activation of LDL-reactive T cells impacts on metabolism and vascular pathobiology. We have developed a T-cell receptor-transgenic mouse model to characterize the effects of immune reactions against LDL. Through adoptive cell transfers and cross-breeding to hypercholesterolemic mice expressing the antigenic human LDL protein apolipoprotein B-100, we evaluate the effects on atherosclerosis. A subpopulation of LDL-reactive T cells survived clonal selection in the thymus, developed into T follicular helper cells in lymphoid tissues on antigen recognition, and promoted B-cell activation. This led to production of anti-LDL immunoglobulin G antibodies that enhanced LDL clearance through immune complex formation. Furthermore, the cellular immune response to LDL was associated with increased cholesterol excretion in feces and with reduced vascular inflammation. These data show that anti-LDL immunoreactivity evokes 3 atheroprotective mechanisms: antibody-dependent LDL clearance, increased cholesterol excretion, and reduced vascular inflammation.

In with the Good and out with the Bad – The Role of SR‐B1 in Lowering Blood Cholesterol Levels

According to the CDC, 1 in 3 adults in the US has high cholesterol, which is linked to cardiovascular disease. Cholesterol, a hydrophobic molecule, is transported in the blood by binding a lipoprotein. Scavenger receptor class B type 1 (SR‐B1), a transmembrane protein that binds high density lipoprotein (HDL) carrying cholesterol, helps transfer cholesterol from HDL into liver cells where it can be excreted in bile. This is important for lowering blood cholesterol levels and reducing the risk of heart disease and stroke. SR‐B1 belongs to a larger family of scavenger receptor proteins that includes lysosome membrane protein 2 (LIMP‐2), and SR‐B1 and LIMP‐2 share structural homology. The structure of the C‐terminal transmembrane domain of SR‐B1, determined through NMR, is composed of three helices with a leucine zipper motif. Mutagenesis studies implicate this leucine zipper motif in dimerization of SR‐B1 and proper receptor function. A crystal structure of LIMP‐2 revealed the existence of a large, primarily hydrophobic cavity that runs the entire length of the protein that suggests a role in the selective transfer of cholesterol into the liver cell. Using 3D printing technology, the Cedarburg SMART (Students Modeling A Research Topic) Team utilized the known structure of LIMP‐2 to investigate structure‐function relationships in SR‐B1. Determining important HDL/SR‐B1 interactions will increase knowledge of how SR‐B1 functions in transferring cholesterol from plasma HDL to the liver for excretion and can lead to the development of medical treatments to increase cholesterol excretion by the liver and prevent heart disease and stroke.Support or Funding InformationThe MSOE Center for BioMolecular Modeling would like to acknowledge and thank the National Institutes of Health Science Education Partnership Award (NIH‐SEPA 1R25OD010505‐01) and the National Institutes of Health Clinical and Translational Science Award (NIH‐CTSA UL1RR031973) for their support in funding the 2017–2018 SMART Team Team program.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Wheat alkylresorcinols reduce micellar solubility of cholesterol in vitro and increase cholesterol excretion in mice

Epidemiological studies have shown that the consumption of whole grains can reduce risk for metabolic disorders. We recently showed that chronic supplementation with wheat alkylresorcinols (ARs) prevents glucose intolerance and insulin resistance with hepatic lipid accumulation induced in mice by a high-fat high-sucrose diet (HFHSD). This study examines the effects of ARs on the micellar solubility of cholesterol in vitro, as well as the effects of transient AR supplementation on faecal lipid excretion and plasma lipid levels in mice. We found that ARs formed bile micelles with taurocholate independently of phospholipids, and dose-dependently decreased the micellar solubility of cholesterol in a biliary micelle model. Transient AR supplementation with HFHSD increased faecal cholesterol and triglyceride contents and decreased plasma cholesterol concentrations. These suggest that one underlying mechanism through which ARs suppress diet-induced obesity is by interfering with the micellar cholesterol solubilisation in the digestive tract, which subsequently decreases cholesterol absorption.

Abstract 256: Global and Hepatocyte-specific Ablation of Bmal1 Induces Hyperlipidemia and Enhances Atherosclerosis

Circadian rhythms controlled by clock genes affect plasma lipids, known risk factors for atherosclerosis. We observed that global ablation of a critical clock gene, Bmal1 , in Apoe –/– and Ldlr –/– mice, and liver-specific ablation of Bmal1 in Apoe –/– (L -Bmal1 –/– Apoe –/– ) mice increases hyperlipidemia and atherosclerosis. In contrast, overexpression of BMAL1 in L-Bmal1 –/– Apoe –/– mice decreases hyperlipidemia and atherosclerosis. Physiologic studies showed that Bmal1 deficiency augments hepatic lipoprotein secretion and diminishes cholesterol excretion to the bile. Molecular studies identified that Bmal1 deficiency reduces expression of Shp, a repressor, and Gata4, an activator. Reductions in Shp increase Mtp expression and lipoprotein production, whereas reductions in Gata4 diminish Abcg5/Abcg8 expression and cholesterol excretion to the bile. SHP expression normalized lipoprotein secretion with no effect on cholesterol excretion to the bile, while GATA4 expression increased cholesterol excretion to the bile and reduced plasma lipids in L-Bmal1 –/– Apoe –/– mice. Taken together, our data indicate that Bmal1 modulates lipoprotein secretion to the plasma and cholesterol excretion to the bile by regulating the expression of Mtp and Abcg5/Abcg8 via Shp and Gata4, and that the loss of Bmal1 promotes hyperlipidemia and atherosclerosis.

The combination of ezetimibe and ursodiol promotes fecal sterol excretion and reveals a G5G8-independent pathway for cholesterol elimination

Previous studies suggest an interdependent relationship between liver and intestine for cholesterol elimination from the body. We hypothesized that a combination of ursodiol (Urso) and ezetimibe (EZ) could increase biliary secretion and reduce cholesterol reabsorption, respectively, to promote cholesterol excretion. Treatment with Urso increased hepatic ABCG5 ABCG8 (G5G8) protein and both biliary and fecal sterols in a dose-dependent manner. To determine whether the drug combination (Urso-EZ) further increased cholesterol excretion, mice were treated with Urso alone or in combination with two doses of EZ. EZ produced an additive and dose-dependent increase in fecal neutral sterol (FNS) elimination in the presence of Urso. Finally, we sequentially treated wide-type and G5G8-deficient mice with Urso and Urso-EZ to determine the extent to which these effects were G5G8 dependent. Although biliary and FNS were invariably lower in G5G8 KO mice, the relative increase in FNS following treatment with Urso alone or the Urso-EZ combination was not affected by genotype. In conclusion, Urso increases G5G8, biliary cholesterol secretion, and FNS and acts additively with EZ to promote fecal sterol excretion. However, the stimulatory effect of these agents was not G5G8 dependent.

The okra skin extract and its cholesterol‐lowering activities ő in vitro study (1045.28)

Okra [Abelmoschus esculentus (L.) Moench], also known as lady’s finger or gumbo, is an edible green vegetable that is widely used in cuisines around the world. It is rich in nutritive components such as dietary fibers, proteins, vitamins, minerals, antioxidants, and polyphenolic compounds. Several studies showed the health benefits of the okra in the prevention of hyperglycemia and hyperlipidemia. This in‐vitro study was aimed to investigate the effect of the okra skin extract on cholesterol‐lowering activities. The inhibitory effects of the extract on pancreatic cholesterol esterase activity and on the cholesterol micellization, also its effect on the binding ability to bile acids, were determined. The results showed that the okra skin extract inhibited pancreatic cholesterol esterase activity in the concentration‐dependent manner (R2=0.817, p <0.05, IC50 = 3.17 mg/mL). Moreover, the extract (ranging from 0.25‐2 mg/mL) also inhibited the cholesterol micellization in the concentration‐dependent manner (R2=0.827, p <0.05). In addition, the okra skin extract showed the ability to bind to bile acids (glycodeoxycholic acid, taurodeoxycholic acid, and taurocholic acid). We found that the binding efficacy of the extract (2 mg/mL) to glycodeoxycholic acid was significantly higher than binding to taurodeoxycholic acid and taurocholic acid (mean±SEM: 16.16±1.26% vs. 10.04±1.02% and 8.76±0.70%, p <0.05, respectively). In conclusion, the okra skin extract exhibited cholesterol‐lowering activities by inhibiting pancreatic cholesterol esterase activity, reducing the efficacy of cholesterol micellization, and binding to bile acids, which may result in delayed cholesterol absorption and increase cholesterol excretion. These findings may be useful for further studies in proposed mechanism on hypolipidemic acitivity of the okra.Grant Funding Source: Grants for Development of New Faculty Staff, Ratchadaphiseksomphot Endowment Fund, CU

Reduction of VLDL secretion decreases cholesterol excretion in niemann-pick C1-like 1 hepatic transgenic mice.

An effective way to reduce LDL cholesterol, the primary risk factor of atherosclerotic cardiovascular disease, is to increase cholesterol excretion from the body. Our group and others have recently found that cholesterol excretion can be facilitated by both hepatobiliary and transintestinal pathways. However, the lipoprotein that moves cholesterol through the plasma to the small intestine for transintestinal cholesterol efflux (TICE) is unknown. To test the hypothesis that hepatic very low-density lipoproteins (VLDL) support TICE, antisense oligonucleotides (ASO) were used to knockdown hepatic expression of microsomal triglyceride transfer protein (MTP), which is necessary for VLDL assembly. While maintained on a high cholesterol diet, Niemann-Pick C1-like 1 hepatic transgenic (L1Tg) mice, which predominantly excrete cholesterol via TICE, and wild type (WT) littermates were treated with control ASO or MTP ASO. In both WT and L1Tg mice, MTP ASO decreased VLDL triglyceride (TG) and cholesterol secretion. Regardless of treatment, L1Tg mice had reduced biliary cholesterol compared to WT mice. However, only L1Tg mice treated with MTP ASO had reduced fecal cholesterol excretion. Based upon these findings, we conclude that VLDL or a byproduct such as LDL can move cholesterol from the liver to the small intestine for TICE.

The Carrageenan Dietary Fiber Suplementation in Feed to Improving Blood Lipid Parameters of Hypercholesterolemic Mice

Carrageenan is example of food with high content of fiber. An experiment was conducted to study the effects of carrageenan supplementations on blood lipid parameters of hypercholesterolemic male mice. The experiment were done at animal cages Departemen of Biology Education, Indonesia University of Education and Fisiology Laboratory Faculty of Veteriner Medicine, Bogor Agricultural Institute on August 2011 until March 2012. The experimental mice were assigned into a completely randomized design with 5 treatments i.e., negative control group; normocholesterolemic mice fed with a standard diet, positive control group; hypercholesterolemic mice fed with a standard diet without carrageenan supplementation, treatments group; hypercholesterolemic mice feds with supplemented with 15%, 30%, and 46% carrageenan. The nonsoluble content of dietary fiber in the experimental treatments were 6.92, 8.75, 10.48, 12.27, and 14.05%, respectively. The parameters measured were body weight, cholesterol levels of blood serum, liver and feces, triglyceride, high density lipoprotein (HDL), low density lipoprotein (LDL) and glucose levels. Supplementation of carrageenan as a source of dietary fiber increased serum HDL concentrations, and decreased body weight, serum cholesterol, triglyceride, and LDL concentrations of hypercholesterolemic male mice without a significant effect on serum glucose consentrations. Hypercholesterolemic mice fed with a supplemented with 46% carrageenan decreased body weight by 7.99%, total serum cholesterol by 18.78%, triglyceride by 17.53%, LDL by 71.33%, and increased HDL by 15.59−20.47%. Carrageenan supplementation reduce liver cholesterol levels by 38.46% and increased cholesterol excretion through feces by 57.07%. Supplementation of 46% carrageenan in hipercholesterolemic fed is effective in improving blood lipid parameters of hypercholesterolemic male mice.

Diet supplementation with beta-carotene improves the serum lipid profile in rats fed a cholesterol-enriched diet

The present study investigated the underlying mechanism associated with the hypocholesterolemic activity of beta-carotene by examining its effects on the serum lipid profile, fecal cholesterol excretion, and gene expression of the major receptors, enzymes, and transporters involved in cholesterol metabolism. Female Fischer rats were divided into three groups and were fed either a control or a hypercholesterolemic diet supplemented or not supplemented with 0.2 % beta-carotene. After 6 weeks of feeding, blood, livers, and feces were collected for analysis, and quantitative real-time polymerase chain reaction (qRT-PCR) was performed. Dietary supplementation with 0.2 % beta-carotene decreased serum total cholesterol, non-HDL cholesterol, the atherogenic index, and hepatic total lipid and cholesterol contents. These changes were accompanied by an increase in the total lipid and cholesterol contents excreted in the feces. The qRT-PCR analyses demonstrated that the hypercholesterolemic diet promoted a decrease in the gene expression of sterol regulatory element-binding protein 2, 3-hydroxy-3-methylglutaryl CoA reductase, and low-density lipoprotein receptor and an increase in the gene expression of peroxisome proliferator-activated receptor α and cholesterol-7a-hydroxylase. The expression of these genes and gene expression of ATP-binding cassette subfamily G transporters 5and 8 were unaffected by beta-carotene supplementation. In conclusion, the decrease in serum cholesterol and the elevation of fecal cholesterol obtained following beta-carotene administration indicate that this substance may decrease cholesterol absorption in the intestine and increase cholesterol excretion into the feces without a direct effect on the expression of cholesterol metabolism genes.

Abstract 396: Acute Hepatic ACAT2 Knockdown Transiently Increases Plasma and Hepatic Free Cholesterol and Fecal Neutral Sterol Excretion

In spite of the advent of statins, atherosclerotic coronary vascular disease (ASCVD) remains the number one killer of Americans. A way to reduce LDL cholesterol, the primary risk factor of ASCVD, is to increase cholesterol excretion from the body. Our group and others have recently found that cholesterol excretion can be facilitated by both biliary and non-biliary pathways. The lipoprotein that delivers cholesterol from the liver through the plasma to the small intestine for transintestinal cholesterol excretion (TICE) is not yet known. We have previously shown that chronic knockdown in mice of hepatic acyl-CoA cholesterol acyltransferase 2 (ACAT2), a cellular enzyme that converts free cholesterol (FC) into cholesteryl ester (CE), appeared to cause the formation of hepatic apoB-containing lipoproteins that preferentially trafficked cholesterol to the small intestine for TICE. We tested the hypothesis that the plasma concentration of TICE-competent, apoB-containing lipoproteins, could be increased by preloading the liver with cholesterol and then acutely depleting the cholesterol by knocking down hepatic ACAT2 with antisense oligonucleotides (ASO). After feeding a high cholesterol (0.2% wt/wt) diet for six weeks, C57BL/6 mice were treated with control non-targeting ASO or ACAT2 ASO for one or two weeks. After only one week of ACAT2 knockdown (ACAT2KD) hepatic ACAT2 protein expression was decreased nearly 80%. This translated into a 50% decrease in hepatic CE concentration in conjunction with a rarely seen 2-fold increase in hepatic FC concentration. Acute hepatic ACAT2KD increased plasma FC levels by 25%, which subsided after two weeks of treatment. The increased plasma FC was primarily associated with large and small LDL. After one week of hepatic ACAT2KD mice had a minor, non-significant increase in biliary cholesterol levels but had a 2-fold increase in fecal neutral sterol (FNS) excretion. In summary our data show that when CE is rapidly cleared from the liver, FNS levels dramatically increase with a transient increase in hepatic and plasma FC levels. We believe that in the ACAT2KD mice the increased plasma FC associated with LDL is feeding into TICE thus resulting in increased FNS.

Reciprocal regulation of cholesterol excretion in apolipoprotein E-null mice by angiotensin II type 1 and type 2 receptor deficiency

AimsThe effects of AT1 and AT2 receptor deficiency on the intake and excretion of cholesterol were examined using atherosclerotic apolipoprotein E-null (ApoEKO) mice. Main methodsApoEKO, AT1a/ApoEKO and AT2/ApoEKO mice received a high-cholesterol diet (HCD: 1.25% cholesterol) for 10days before sampling. Key findingsPlasma total cholesterol level was lower in AT1a/ApoEKO mice and higher in AT2/ApoEKO mice than in ApoEKO mice with a high cholesterol intake. In these mice, cholesterol content in feces was higher in AT1a/ApoEKO mice and lower in AT2/ApoEKO mice than in ApoEKO mice. Moreover, cholesterol content in bile tended to be higher in AT1a/ApoEKO mice and lower in AT2/ApoEKO mice than in ApoEKO mice, while a significant difference was observed only between AT1a/ApoEKO and AT2/ApoEKO mice. Cholesterol content and expression of HMG-CoA reductase and LDL receptor in liver were not different among the groups. Similar but weaker changes were also observed with a normal standard diet. Treatment with an AT1 receptor blocker, irbesartan, increased cholesterol content in bile and tended to increase cholesterol excretion into feces in ApoEKO mice with HCD. SignificanceThese results suggest that AT1 and AT2 receptor stimulation was involved in the regulation of cholesterol excretion into bile and feces, and that the regulation acted reciprocally in a cholesterol overload condition with HCD.