Hepatic ABCG8 Research Articles

Shatianyu (Citrus grandis L. Osbeck) Flavonoids and Dietary Fiber in Combination Are More Effective Than Individually in Alleviating High-Fat-Diet-Induced Hyperlipidemia in Mice by Altering Gut Microbiota

This study was aimed at exploring the separate and combined anti-hyperlipidemic effect of Shatianyu (Citrus grandis L. Osbeck) flavonoids (SPFEs) and DF (SPDF) on HFD-fed mice after 14-week administration in diet, together with the possible microbiota-mediated mechanisms. SPFEs and SPDF were more effective together than separately in improving serum lipid profiles, decreasing hepatic lipid accumulation, and upregulating the expression of hepatic CPT1a, CYP7A1, ABCG5, and ABCG8. Butyrate has been previously proved to have an anti-hyperlipidemic effect. The fecal butyrate contents were negatively correlative with serum/liver lipid but positively correlated with fecal total bile acids levels, and SPDF + SPFEs had the most fecal butyrate in this study. SPDF or SPFEs enriched microbiota related to acetic and propionic acids production, while SPDF + SPFEs also bloomed norank_f_Muribaculaceae, Dubosiella, Lachnoclostridium, and norank_f_Eubacterium_coprostanoligenes_group, which were positively correlated to fecal butyrate contents. Thus, SPFEs and SPDF might alleviate hyperlipidemia synergistically by regulating microbiota to produce butyrate, thereby regulating lipid metabolism.

Microsomal triglyceride transfer protein inhibitor lomitapide-induced liver toxicity is ameliorated by Triiodothyronine treatment following improved bile homeostasis and β-oxidation

Dyslipidemia or its severe version like familial hypercholesterolemia causes a high risk for cardiovascular diseases. Lomitapide, a microsomal triglyceride transfer protein inhibitor, is approved to treat familial hypercholesterolemia, associated with liver fat accumulation. In this work, we investigated the effect of the combination of lomitapide and triiodothyronine (T3) in Zucker fatty rats. Lomitapide (1 mg/kg, PO), or T3 (13 μg/kg, PO), or their combination, were given to these rats once daily for fourteen days. Body weight and food intake were recorded once daily during the treatment period. Serum and hepatic lipids, glucose tolerance, serum aminotransferases, bile fluids, hepatic gene expression, and liver histology were assessed at the end of the treatment. Lomitapide treatment reduced body weight, food intake, glucose intolerance, and serum lipids, and elevated serum aminotransferases and liver lipids. When combined with T3, lomitapide showed an enhanced reduction in body weight, food intake, serum cholesterol, serum LDL, and glucose intolerance. The combination treatment increased bile flow rate and biliary cholesterol excretion rate. Combining T3 with lomitapide attenuated the elevation of serum aminotransferases and liver lipids. Hepatic ABCB11, ABCG5, ABCG8, CYP7A1, CPT1, and ACOX1 expressions were increased with combination treatment. Histological analysis indicated that T3 attenuated hepatic fat accumulation caused by lomitapide. These data suggests that combining lomitapide with T3 may reduce lomitapide-induced hepatic toxicity and provide additional benefits in obesity and glucose intolerance.

Lycopene supplementation does not change productive performance but lowers egg yolk cholesterol and gene expression of some cholesterol-related proteins in laying hens

ABSTRACT 1. This work examined the effects of purified lycopene (LYC) supplementation or a source of LYC as tomato powder (TP) on productive performance, egg yolk cholesterol levels as well as gene expression related to mechanism and regulation of cholesterol. 2. One hundred and fifty laying hens (Lohman LSL, hybrid) were randomly divided into one of three treatments, with 10 replicates of five hens per cage, totalling 50 hens per treatment. The hens were fed either a standard diet (control) or a standard diet supplemented with 20 mg purified lycopene/kg diet (LYC) or an equal amount of lycopene-containing tomato powder (TP) for 12 weeks. 3. Feed consumption, egg production, and feed efficiency remained similar among treatments (P ≥ 0.27). Supplementing lycopene, either as a purified form or in TP, increased the levels of serum and egg yolk lycopene and reduced serum and egg yolk cholesterol concentrations (P < 0.001). Supplementation in either form decreased gene expression for intestinal NPC1L1, MTP, ACAT2, hepatic SREBP1c, ACLY, and LXRα but increased hepatic ABCG5 and ABCG8 (P < 0.001). 4. The results of the present work revealed that egg yolk cholesterol metabolism is regulated by the modulation of a group of genes, particularly with LYC supplementation.

Lycopene Supplementation Either Purified or as in Tomato Powder to the Diet of Laying Hens Lowers Egg Yolk Cholesterol by Modulation of Sterol Transporters

Abstract Objectives The objective of this work was to investigate the effects of dietary supplementation of purified lycopene (LYC) or a source of LYC as in tomato powder (TP) on live hen performance, egg yolk cholesterol concentrations as well as the gene expressions related to mechanism and regulation of cholesterol, namely Niemann-Pick C1-like 1 protein (NPC1L1), acyl-CoA: cholesterol acyltransferase 2 (ACAT2), microsomal triacylglycerol transport protein (MTP), ATP binding cassette transporters sub-family G member 5 and 8 (ABCG5/8), ATP citrate lyase (ACLY), liver X receptor alpha (LXRα) and sterol regulatory element-binding proteins (SREBP1c). Methods A total of 150 20-week-old white laying hens were divided into one of 3 treatments, with 10 replicates of 5 hens per cage, totaling 50 hens per treatment. The birds were fed either a basal diet (Control) or basal diet supplemented with 20 mg purified lycopene/kg diet (LYC) or an equal amount of lycopene-containing tomato powder (TP) for 12 weeks. Results Feed intake, egg production and feed conversion ratio remained similar among treatments (P ≥ 0.27). However, egg weights from hens fed a diet supplemented with lycopene particularly the purified form were greater (P = 0.036). Supplementing lycopene either purified or as in TP increased the concentrations of serum and egg yolk lycopene but decreased serum and egg yolk cholesterol concentrations (P &amp;lt; 0.001). Supplementing LYC purified or as in TP decreased the gene expression of intestinal NPC1L1, MTP, ACAT2, hepatic SREBP1c, ACLY, and LXRα but increased hepatic ABCG5 and ABCG8 (P &amp;lt; 0.001). The gene expressions were more pronounced with TP supplements compared with that of the LYC supplements. Conclusions The results of the present work revealed that egg yolk cholesterol metabolism is downregulated through decreased activities of intestinal NPC1L1, MTP, ACAT2, hepatic SREBP1c, ACLY, and LXRα but upregulated with increased hepatic activities of ABCG5 and ABCG8. Funding Sources Small and Medium Enterprises Development Organization of Turkey (KOSGEB) Turkish Academy of Sciences.

Sitosterolemia (phytosterolemia)

Sitosterolemia or phytosterolemia is arare autosomal recessive hereditary lipid storage disorder. It is caused by homozygous or compound heterozygous mutations in one of the two ABCG5 and ABCG8 genes encoding the intestinal and hepatic heterodimer ABCG5 (sterolin 1)/ABCG8 (sterolin 2) efflux transporters. These mutations lead to intestinal hyperabsorption and reduced hepatic secretion of cholesterol and plant sterols with subsequent accumulation of phytosterols and cholesterol in plasma and deposition in tissue (xanthoma). Phytosterols are found mainly in vegetable oils, margarine, nuts, grains, soybeans and avocados. Patients with sitosterolemia show extreme phenotypic heterogeneity from almost asymptomatic individuals to those with combined severe hypercholesterolemia at ayoung age, leading to increased atherosclerosis and premature cardiac death. Early abnormalities include hemolytic anemia with stomatocytosis, macrothrombocytopenia and splenomegaly. In addition to strict avoidance of phytosterol-containing foods, the use of the sterol absorption inhibitor ezetimibe, possibly in combination with the bile acid-binding resin cholestyramine, is the most effective treatment option.

FMO3 and its metabolite TMAO contribute to the formation of gallstones

Trimethylamine-N-oxide (TMAO) is a metabolite derived from trimethylamine (TMA), which is first produced by gut microbiota and then oxidized by flavin-containing monooxygenase 3 (FMO3) in the liver. TMAO may contribute to the development of diseases such as atherosclerosis because of its role in regulating lipid metabolism. In this study, we found that high plasma TMAO levels were positively associated with the presence of gallstone disease in humans. We further found increased hepatic FMO3 expression and elevated plasma TMAO level in a gallstone-susceptible strain of mice C57BL/6J fed a lithogenic diet (LD), but not in a gallstone-resistant strain of mice AKR/J. Dietary supplementation of TMAO or its precursor choline increased hepatic FMO3 expression and plasma TMAO levels and induced hepatic canalicular cholesterol transporters ATP binding cassette (Abc) g5 and g8 expression in mice. Up-regulation of ABCG5 and ABCG8 expression was observed in hepatocytes incubated with TMAO in vitro. Additionally, in AKR/J mice fed a LD supplemented with 0.3% TMAO, the incidence of gallstones rose up to 70% compared with 0% in AKR/J mice fed only a LD. This was associated with increased hepatic Abcg5 and g8 expression induced by TMAO. Our study demonstrated TMAO could be associated with increased hepatic Abcg5/g8 expression, biliary cholesterol hypersecretion and gallstone formation.

Abstract 629: FGF15/19 Upregulates Hepatic ABCG5 and ABCG8 to Promote Biliary Cholesterol Secretion

Background: Elevated hepatic cholesterol is thought to contribute to the development of nonalcoholic fatty liver disease, a condition highly associated with cardiovascular risk factors. The ABCG5 and ABCG8 (G5G8) heterodimer is responsible for up to 90% of biliary cholesterol secretion and is a potential therapeutic target for promoting cholesterol elimination. We have previously demonstrated that ursodiol (UDCA), a pharmacologic bile acid, increases G5G8 protein expression and biliary cholesterol secretion. However, whole body cholesterol elimination is minimized likely due to simultaneous suppression of bile acid synthesis through upregulation of FGF15/19. The objectives of this study are to determine whether FGF15/19 regulates G5G8 and determine whether UDCA requires FGF15/19 signaling in order to upregulate G5G8. Methods: Mice were injected with two doses of FGF19 or carrier (PBS) 1μg/g body weight within an 8-hour treatment window. A separate group of wild type (WT) and G5G8 knockout (KO) mice were similarly injected with FGF19. In another experiment, WT mice were fed chow or UDCA-supplemented diet in the absence or presence of FGF15/19 signaling inhibition which was achieved by FGFR4 antisense oligonucleotide (ASO) supplied by Ionis Pharmaceuticals. In all experiments, body weight, liver weight, bile flow rate and plasma, hepatic and biliary lipids were measured. Immunoblotting of G5G8 and real-time PCR of genes involved in cholesterol metabolism were also conducted. Results: Mice injected with FGF19 had increased biliary lipids (PBS: 5.287±0.5720, FGF19: 8.098±0.6114, n=6), decreased Cyp7a1 (PBS: 1.021±0.1064 FGF19: 0.07787±0.01345 n=5-7) and Cyp8b1 (PBS: 1.018±0.09846, FGF19: 0.2647±0.05609, n=5-7) expression, and increased G5G8 protein expression compared to mice injected with PBS. In G5G8 KO mice injected with FGF19, there was only a small increase in plasma free cholesterol (WT: 51.96±2.098, KO: 62.24±2.562, n=4) and no other significant changes in cholesterol metabolism compared to wild type mice injected with FGF19. Conclusion: In conclusion, FGF15/19 suppresses bile acid synthesis and post-transcriptionally upregulates G5G8. However, in the absence of G5G8, FGF15/19 did not disrupt cholesterol metabolism.

Abstract 439: Atherosclerosis Development is Reduced in Mice With Blunted Biliary Cholesterol Secretion

Excessive accumulation of cholesterol in the arteries drives atherosclerosis development. It is believed that biliary cholesterol secretion is crucial for eliminating excess cholesterol from the body via reverse cholesterol transport. In the current study, we wanted to determine the impact of reduced biliary cholesterol secretion on atherosclerosis development in mice. Decreased biliary cholesterol secretion was achieved by hepatic over-expression of human NPC1L1 (L1Tg mice) combined with knockdown of hepatic ABCG5/G8 function using an ABCG8 antisense oligonucleotide (ASO). LDLR-/- and LDLR-/-/L1Tg mice received either control or ABCG8 ASO and were fed a high fat (42% Kcal)/low cholesterol diet (0.015% wt/wt) for 20 weeks. As expected, L1Tg mice and mice with hepatic ABCG8 knockdown had an &gt;70% reduction in biliary cholesterol. The dramatic decrease in biliary cholesterol did not increase plasma cholesterol, and in fact mice with hepatic ABCG8 knockdown had reduced VLDL cholesterol. Even more surprising, aortic atherosclerosis was significantly decreased in mice with compromised biliary cholesterol secretion. LDLR-/-/L1Tg treated with ABCG8 ASO had a &gt;90% reduction in biliary cholesterol yet had ~70% less atherosclerosis compared to LDLR-/- controls. Moreover, reducing biliary cholesterol had no impact on macrophage reverse cholesterol transport, fecal excretion of neutral sterol, and hepatic expression of genes involved in cholesterol synthesis (HMG CoA reductase/synthase) and HDL metabolism (ABCA1 and SR-BI). These results indicate that atherosclerosis development can be decreased by shunting cholesterol away from biliary secretion and potentially towards trans-intestinal cholesterol excretion or bile acid synthesis.

Components characterization of total tetraploid jiaogulan (Gynostemma pentaphyllum) saponin and its cholesterol-lowering properties

This study characterized chemical structures of tetraploid jiaogulan saponins, and investigated their cholesterol-lowering effects and mechanisms in hamsters fed a high-fat diet (HFD). Nine saponins, including five reported for the first time, were obtained from total jiaogulan saponins (TJS) and elucidated for their chemical structures according to 2D NMR and HR-MS data. Administration of TJS effectively decreased plasma total cholesterol by 17.4% and 32.6%, triacylglycerols by 22.8% and 47.7% and LDL-C by 22.0% and 40.2%, respectively. Moreover, supplementation with TJS significantly increased faecal excretion of total cholesterol and bile acids by 43.8% and 64.4%, respectively. TJS significantly up-regulated intestinal mRNA levels of ABCG5/8, LXRα, hepatic mRNA CYP7A1 and ABCG5 in hamsters on HFD. In addition, TJS decreased cholesterol micelle solubility and suppressed cholesterol uptake in cultured Caco-2 cells. Taking together, TJS may reduce plasma cholesterol by increasing faecal cholesterol excretion and through modulation of genes involved in cholesterol absorption and metabolism.

Abstract 131: Restoration of ER Stress and Induction of FGF15/19 Independently Rescue ABCG5 ABCG8 Sterol Transporter

Mice lacking leptin (ob/ob) or its receptor (db/db) are obese, insulin resistant and have reduced levels of biliary cholesterol due, in part, to reduced levels of hepatic ABCG5 ABCG8 (G5G8). Chronic leptin replacement restores G5G8 abundance and increases biliary cholesterol concentrations, but the molecular mechanism responsible for G5G8 regulation remains unclear. In the current study, we conducted a series of experiments to address potential mechanisms. To determine if leptin signaling directly regulates hepatic G5G8 abundance, we acutely replaced leptin in ob/ob mice and deleted hepatic leptin receptors in lean mice. Neither manipulation altered G5G8 abundance or biliary cholesterol. Similarly, hepatic vagotomy had no effect on G5G8. Alternatively, the G5G8 protein complex may be decreased due to compromised ER stress. It has been previously reported that tauroursodeoxycholate (TUDCA) alleviates ER stress. It also increases G5G8 and biliary cholesterol in both lean and db/db mice. The ER chaperone protein, glucose regulated protein 78-kDa (GRP78) can restore ER function and reduce unfolded protein response (UPR) signaling. Therefore, we tested the hypothesis that expression of GRP78 could rescue G5G8 in db/db mice. Adenovirus encoding GRP78 was administered to db/db mice and the effect on hepatic G5G8 was determined. G5 and G8 proteins and biliary cholesterol were increased in the absence of changes in mRNAs encoding either protein. However, TUDCA has also been shown to induce FGF15. In several models of bile acid feeding, FGF15/19 is stimulated in ileum and activates its receptor in liver to repress bile acid synthesis. Simultaneously, G5G8 and biliary cholesterol secretion are elevated. To determine if FGF15/19 had a direct effect on hepatic G5G8, we injected C57BL/6 mice with recombinant FGF19. CYP7A1 and CYP8B1 mRNA expression were both strongly suppressed, whereas G5G8 increased at both mRNA and protein levels. In conclusion, G5G8 can be rescued in ob/ob and db/db mice through multiple mechanisms that include restoration of ER functions and FGF15/19 signaling. Counter regulation of CYP7A1, CYP8B1, and G5G8 by FGF15/19 allows for the maintenance of hepatic sterol elimination in the face of expanded bile acid pool.

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.

Liver-specific induction of Abcg5 and Abcg8 stimulates reverse cholesterol transport in response to ezetimibe treatment

ObjectivePrevious studies have shown ezetimibe treatment results in a 2–6-fold increase in reverse cholesterol transport (RCT). However, recent sterol balance studies question the role of biliary sterol secretion in RCT, and challenge the hypothesis that ezetimibe increases RCT through decreased absorption of biliary cholesterol in the intestine. We set out to determine whether ezetimibe may increase RCT by mechanisms that are independent of its well-established inhibition of intestinal cholesterol absorption. MethodsC57BL/6J, Npc1l1-KO, and/or Abcg8-KO mice were fed a chow diet with or without ezetimibe and fecal [14C]-neutral and [14C]-acidic sterols were measured to examine macrophage-to-feces RCT. We measured the expression of RCT related genes in the liver and jejunum in these mice. To confirm our significant gene expression findings, we utilized primary human hepatocytes cultured with or without a glucuronated metabolite of ezetimibe. ResultsOur studies revealed that treatment with ezetimibe was associated with increased expression of hepatic Abcg5 and Abcg8. Ezetimibe did not directly affect expression in the liver, but this expression was due to the inhibition of intestinal cholesterol absorption. This conclusion was supported by the absence of an ABCG5/ABCG8 expression response to treatment with an ezetimibe metabolite in primary human hepatocytes. Finally, we found that the ezetimibe-dependent stimulation of RCT was attenuated in the absence of Abcg8. ConclusionsOur study is the first to demonstrate ezetimibe treatment cooperatively stimulated macrophage-to-feces RCT by indirectly increasing liver Abcg5/Abcg8 expression in addition to its known suppression of intestinal cholesterol absorption.

Chronic unpredictable mild stress combined with a high-fat diets aggravates atherosclerosis in rats.

BackgroundDepression and high-fat diet are both known as independent risk factors for atherosclerosis and other cardiovascular diseases, suggesting the interaction of psychological and physiological factors in the development of these diseases. The liver is a crucial organ that facilitate lipid metabolism especially in reverse cholesterol transport (RCT), while according to the theory of Traditional Chinese Medicine, depression as a kind of psychological stress has an influence on hepatic function. So there seem to be some links between depression and lipid metabolic disorders.MethodsTo investigate these links, we separately treated rats with chronic unpredictable mild stress (CMS) and/or a high-fat diet (HD) to evaluate the development of atherosclerosis and the expression of hepatic ABCG8, ABCG5, SR-BI, CYP7A1, LXRα, and LCAT which were associated with reverse cholesterol transport.ResultsThis study provided evidence that high-fat diet greatly decreased these genes expression related to RCT while chronic stress alone tended to promote RCT. Chronic unpredictable mild stress combined with a high-fat diet attenuated RCT and aggravated atherogenesis.ConclusionsThese observations suggested that chronic psychological stress alone is virtually propitious to lipid metabolism, however when under a condition of high-fat diet, it deteriorated atherosclerotic plague and did harm to RCT.

Plasma and hepatic cholesterol-lowering effects of tomato pomace, tomato seed oil and defatted tomato seed in hamsters fed with high-fat diets

The cholesterol-lowering effects of tomato pomace (TP), tomato seed oil (TSO) and defatted tomato seed (DTS) were determined in male Golden Syrian hamsters. Hamsters fed high-fat diets containing 10% TSO or 18% DTS were compared to a diet containing 10% corn oil and 10% microcrystalline cellulose (control 1), 42% TP were compared to 25% microcrystalline cellulose (control 2). TP, TSO and DTS reduced hepatic total cholesterol (TC) content. DTS also lowered plasma TC and low-density lipoprotein cholesterol (LDL-C) concentrations. Fecal excretion of lipid, bile acid and cholesterol increased in the DTS group compared to control 1. DTS-fed hamsters had higher levels of hepatic CYP7A1, CYP51, ABCB11, and ABCG5 gene expression than control, suggesting both hepatic bile acid and cholesterol synthesis increased due to increased fecal excretion of bile acid and cholesterol. The results suggest that protein, dietary fibre or phenolic compounds in DTS may be responsible for plasma cholesterol decrease.

Isolation of biliary lipid carrying vesicles, analysis of their biochemical properties and hepatic ABCG5 mRNA expression in diosgenin-fed rats

Objective: An attempt was made to isolate vesicles, rich in biliary-type lipid from livers of ratsfed with diosgenin, which is reported to increase cholesterol carrying vesicles in hepatocytes, and to determine their lipid, alkaline phosphodiesterase I, protein status and hepatic ATP-binding cassette half-transporter genes 5/8 (ABCG5/ABCG8) expression. Material and Methods: The livers were removed, homogenized, subjected to centrifugation, and the microsomal fraction was obtained. This microsomal fraction was then loaded onto a 12% self generating gradients of OptiPrep TM in a Beckman Vti 65 vertical-tube rotor and centrifuge at 350000 xg for 90 min at 4°C. The gradient fractions were analysed for total phospholipid, cholesterol, protein and alkaline phosphodiesterase I (PDE). Results: There were no differences in total phospholipid, cholesterol and protein contents of the subcellular fractions of livers from control and diosgenin fed rats. However, PDE activity was significantly lower in some subcellular fractions in diosgenin-fed rats compared to controls. The gradient fractions with density 1.05-1.07 g/ml had increased amounts of cholesterol, PDE activity and some phospholipids, but contained very little protein. However, the gradient fractions with density 1.09-1.23 g/ml were significantly rich in cholesterol, phospholipids and protein, but not PDE activity, suggesting another population of vesicles. Hepatic ABCG5 mRNA expression was increased in diosgenin-fed rats compared with the control group, although, no significant difference was found in hepatic ABCG8 mRNA expression between control and diosgenin-fed rats. Conclusion: These findings suggested that ABCG5 is involved in diosgenin induced biliary cholesterol secretion and may provide an insight into mechanisms involved in biliary lipid transport.

Simvastatin reduces atherogenesis and promotes the expression of hepatic genes associated with reverse cholesterol transport in apoE-knockout mice fed high-fat diet

BackgroundStatins are first-line pharmacotherapeutic agents for hypercholesterolemia treatment in humans. However the effects of statins on atherosclerosis in mouse models are very paradoxical. In this work, we wanted to evaluate the effects of simvastatin on serum cholesterol, atherogenesis, and the expression of several factors playing important roles in reverse cholesterol transport (RCT) in apoE-/- mice fed a high-fat diet.ResultsThe atherosclerotic lesion formation displayed by oil red O staining positive area was reduced significantly by 35% or 47% in either aortic root section or aortic arch en face in simvastatin administrated apoE-/- mice compared to the control. Plasma analysis by enzymatic method or ELISA showed that high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) contents were remarkably increased by treatment with simvastatin. And plasma lecithin-cholesterol acyltransferase (LCAT) activity was markedly increased by simvastatin treatment. Real-time PCR detection disclosed that the expression of several transporters involved in reverse cholesterol transport, including macrophage scavenger receptor class B type I, hepatic ATP-binding cassette (ABC) transporters ABCG5, and ABCB4 were induced by simvastatin treatment, the expression of hepatic ABCA1 and apoA-I, which play roles in the maturation of HDL-C, were also elevated in simvastatin treated groups.ConclusionsWe demonstrated the anti-atherogenesis effects of simvastatin in apoE-/- mice fed a high-fat diet. We confirmed here for the first time simvastatin increased the expression of hepatic ABCB4 and ABCG5, which involved in secretion of cholesterol and bile acids into the bile, besides upregulated ABCA1 and apoA-I. The elevated HDL-C level, increased LCAT activity and the stimulation of several transporters involved in RCT may all contribute to the anti-atherosclerotic effect of simvastatin.

Soy Protein regulates differently reverse cholesterol transport in liver and ileum in mice.

Liver X alpha‐receptor (LXRα) is activated by oxysterols that regulates ABCG5, ABCG8 and ABCA1 gene expression involved in the reverse cholesterol transport (RCT). Up‐regulation increases biliary cholesterol secretion and limits cholesterol (CH) absorption. Studies in rats have demonstrated that soy protein (SP) has hypocholesterolemic effect through an increase in bile acid secretion. In the present study, we evaluated the effect of a high CH SP or casein diet on the expression of ABCG5, ABCG8, ABCA1 transporters in ileum and liver of wild‐type and LXRα knockout mice. We demonstrated that the absence of hepatic LXRα increased hepatic lipid concentration particularly with the high CH diets. Liver of mice fed with SP showed less macro‐vesicular steatosis, lipid accumulation and inflammatory infiltration independently of genotype and presence of CH in the diet. The absence of LXRα greatly reduced hepatic ABCG5, ABCG8 and ABCA1 mRNA expression with respect to the amount of hepatic CH concentration. However, the expression of these transporters in ileum of wild‐type group was higher in the SP+CH group than the group fed casein+CH. In addition, animals fed with SP+CH showed a higher excretion of fecal bile acids compared to casein+CH group. These results indicates that SP increases bile acid excretion through an increase in the ABC transporters despite the lack of LXRα. Supported by CONACYT Grant No 84786 (to O.G)

Identification of Novel Pathways That Control Farnesoid X Receptor-mediated Hypocholesterolemia

Farnesoid X receptor (FXR) plays important regulatory roles in bile acid, lipoprotein, and glucose homeostasis. Here, we have utilized Fxr(-/-) mice and mice deficient in scavenger receptor class B type I (SR-BI), together with an FXR-specific agonist and adenovirus expressing hepatocyte nuclear factor 4alpha or constitutively active FXR, to identify the mechanisms by which activation of FXR results in hypocholesterolemia. We identify a novel pathway linking FXR to changes in hepatic p-JNK, hepatocyte nuclear factor 4alpha, and finally SR-BI. Importantly, we demonstrate that the FXR-dependent increase in SR-BI results in both hypocholesterolemia and an increase in reverse cholesterol transport, a process involving the transport of cholesterol from peripheral macrophages to the liver for excretion into the feces. In addition, we demonstrate that FXR activation also induces an SR-BI-independent increase in reverse cholesterol transport and reduces intestinal cholesterol absorption. Together, these data indicate that FXR is a promising therapeutic target for treatment of hypercholesterolemia and coronary heart disease.

Epigenetic changes in gene expression: focus on “The liver X-receptor gene promoter is hypermethylated in a mouse model of prenatal protein restriction”

the term epigenetics was first coined in 1942 by Waddington ([20][1]) to describe the interaction of genes with their environment during development that gives rise to a phenotype. Today, the term epigenetics is used when describing a phenotype that occurs in a manner outside conventional genetic

Dietary Phytosterols and Phytostanols Alter the Expression of Sterol-Regulatory Genes in SHRSP and WKY inbred Rats

Background/Aims: We elucidated the molecular mechanism(s) underlying sterol trafficking by investigating alterations in gene expression in response to increased retention of dietary phytosterols and phytostanols in stroke-prone spontaneously hypertensive (SHRSP) and normotensive Wistar Kyoto (WKY) inbred rats. Methods: SHRSP and WKY inbred rats were fed a control diet or a diet supplemented with phytosterols or phytostanols (2 g/kg diet). Results: Intake of phytosterols and phytostanols increased their incorporation in plasma, red blood cells, liver, aorta and kidney, but decreased cholesterol levels in liver and aorta in both rat strains. Phytosterol intake up-regulated mRNA expression of intestinal Npc1l1 and Abcg8, and hepatic Abcg5, Abca1, Cyp27a1 and Hmgcr. Phytostanol intake up-regulated Npc1l1 and Srebp2, but down-regulated Abcg5 mRNA expression in small intestine. Phytostanols also up-regulated Abca1 expression in SHRSP rats, but down-regulated Abca1 expression in WKY inbred rats. Compared to phytosterols, dietary phytostanols reduced phytosterol levels in plasma, red blood cells, and kidney, as well as altered mRNA levels of hepatic Abca1,Cyp27a1, and Hmgcr and intestinal Abcg5/8, Hmgcr and Srebp2. Conclusions: Altered expression of multiple sterol-regulatory genes may contribute to the incorporation and cholesterol-lowering actions of phytosterols and phytostanols. Phytosterols and phytostanols may act through different mechanism(s) on cholesterol and phytosterol/phytostanol trafficking.