Inhibition of Ceramide Decreased the Expression of ATP-Binding Cassette Transporter G5/8 mRNA in an Animal Model of Cholesterol Gallstone

2017 ◽  
Vol 35 (5) ◽  
pp. 439-443 ◽  
Author(s):  
Hyo Jung Kim ◽  
Jae Seon Kim ◽  
Seikwan Oh ◽  
Hwan-Soo Yoo
Keyword(s):  
Cholesterol Gallstone ◽  
Specific Inhibitor ◽  
Gallstone Formation ◽  
Normal Group ◽  
Atp Binding ◽  
Chow Diet ◽  
Mrna Levels ◽  
Lithogenic Diet ◽  
Increased Risk ◽  
Atp Binding Cassette

Background: The increased risk of gallstone has been reported in patients with ATP-binding cassette (ABC) transporter polymorphism. The half-transporters ABCG5 and ABCG8 mediate the efflux of cholesterol in hepatocytes and the intestine. We investigated whether ceramide plays a role in cholesterol efflux through the ABC transporters. Methods: Six-week-old C57BL/6J mice were assigned to 3 groups. The normal group (n = 5) was fed a normal chow diet, the cholesterol group (n = 10) was fed a lithogenic diet, and the myriocin group (n = 15) was fed the lithogenic diet and myriocin, a specific inhibitor of serine-palmitoyl transferase. After 6 weeks, the ABCG5 and ABCG8 transporters were analyzed. Results: The rate of cholesterol gallstone formation in cholesterol group was also higher than that in normal and myriocin groups (0, 70, and 40%, respectively). ABCG5 and ABCG8 mRNA levels were significantly increased in cholesterol group and less increased in myriocin group, relative to that in normal group (p < 0.05). Conclusions: The inhibition of ceramide biosynthesis by myriocin suppressed gallstone formation and ABCG5/8 mRNA expression. We expect that ceramide's role as a regulator of the ABCG5/8 transporter might be linked to cholesterol gallstone formation.

scholarly journals Sterol carrier protein 2 participates in hypersecretion of biliary cholesterol during gallstone formation in genetically gallstone-susceptible mice

1998 ◽  
Vol 336 (1) ◽  
pp. 33-37 ◽  
Author(s):  
Michael FUCHS ◽  
Frank LAMMERT ◽  
David Q.-H. WANG ◽  
Beverly PAIGEN ◽  
Martin C. CAREY ◽  
...  
Keyword(s):  
Steady State ◽  
Cholesterol Gallstone ◽  
Gallstone Formation ◽  
Carrier Protein ◽  
Mrna Levels ◽  
Sterol Carrier Protein ◽  
Biliary Cholesterol ◽  
Lithogenic Diet ◽  
Sterol Carrier Protein 2 ◽  
Akr Mice

In inbred mice, susceptibility to cholesterol gallstone disease is conferred by Lith genes, which in part promote hypersecretion of cholesterol into bile in response to a high-fat/cholesterol/cholic acid (lithogenic) diet. Because cytosolic sterol carrier protein 2 (SCP2) is believed to participate in cellular cholesterol trafficking and is elevated in the liver cytosol of cholesterol gallstone patients, we defined the hepatic expression of SCP2 during cholesterol gallstone formation in gallstone-susceptible C57L and gallstone-resistant AKR mice fed the lithogenic diet. Steady-state cytosolic SCP2 levels in C57L, but not AKR mice increased as a function of time and were correlated positively with biliary cholesterol hypersecretion, cholesterol saturation indices of gall-bladder biles and the appearance of liquid and solid cholesterol crystals leading to gallstone formation. Steady-state mRNA levels increased co-ordinately, consistent with regulation of SCP2 expression at the transcriptional level. Our results suggest that overexpression of SCP2 contributes to biliary cholesterol hypersecretion and the pathogenesis of gallstones in genetically susceptible mice. Because of the different chromosomal localizations of the Lith and Scp2 genes, we postulate that Lith genes control SCP2 expression indirectly.

Increased risk of cholesterol gallstone formation in subjects with apolipoprotein E4 genotype

1998 ◽  
Vol 10 (12) ◽  
pp. A8
Author(s):  
K. J. van Erpecum ◽  
P. Portincasa ◽  
E. R.M. Eckhardt ◽  
B. J.M. van de Heijning ◽  
A. K. Groen ◽  
...  
Keyword(s):  
Cholesterol Gallstone ◽  
Gallstone Formation ◽  
Apolipoprotein E4 ◽  
Increased Risk

Abstract 276: Shockwave Reduces Macrophage Foam Cell Formation Via Increased Expression of ATP Binding Cassette Transporters.

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Wonkyoung Cho ◽  
Young Eun Yoon ◽  
Kihwan Kwon ◽  
Young Mi Park
Keyword(s):  
Western Blot ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Atp Binding ◽  
Mrna Levels ◽  
Macrophage Foam Cell ◽  
Migration Assay ◽  
Intracellular Cholesterol ◽  
Atp Binding Cassette

Background: Excessive lipid accumulation by macrophages plays a crucial role in atherosclerosis. Foam cells are generated by uncontrolled uptake of modified LDL, especially oxidized LDL (oxLDL), and/or impaired cholesterol efflux mediated by ATP-binding cassette (ABC) family transporters, ABCA-1 and ABCG-1. Shockwave, elicited by transient pressure disturbance, have been used for extracorporeal lithotripsy or for treating musculoskeletal disorders. Our current study suggests an evidence that shockwave may have anti-atherogenic effect by inhibiting foam cell formation. Methods/Results: Murine peritoneal macrophages were exposed to shockwaves at 0.04 mJ/mm 2 with 1000 impulses, lysed after 6, 18 and 24 hours, and tested for expression of ABCA-1 and ABCG-1. The western blot showed that shockwave induced 2.0-2.8 fold increase of ABCA-1 and ABCG-1 within 18-24 hours. mRNA levels of ABCA-1 and ABCG-1 were also increased by shockwave with 2.0 fold of peak increase in 18 hours. The increased expression of ABCA-1 and ABCG-1 was mediated by phosphorylation of ERK 1/2 (Tyr204). Western blot analysis revealed that shockwave induced phosphorylation of ERK 1/2 (Tyr204) in murine macrophages. Shockwave-induced increase of ABCA-1 and ABCG-1 was blocked by U0126 (40µM), a specific inhibitor for ERK. Oil-red O staining showed that macrophages exposed to shockwave had 25% less intracellular lipid droplets. Intracellular cholesterol measured by cholesterol oxidase and esterase revealed that macrophages exposed to shockwave had 23% less intracellular cholesterol when incubated with oxLDL (50µg/ml) for 16 hours. In vitro migration assays including modified Boyden chamber migration assay and scratch wound healing migration assay showed that macrophages exposed to shockwave had 1.2 fold more migration and had diminished migration-inhibitory effect of oxLDL. Conclusions: Shockwave reduces macrophage foam cell formation via ERK-mediated increase of ABCA-1 and ABCG-1 mediating lipid efflux and promotes macrophage migration which may induce macrophage egress from atherosclerotic lesion. Our study suggests anti-atherogenic effects of shockwave as a potential treatment modality for atherosclerosis.

scholarly journals Quantitative trait loci mapping for cholesterol gallstones in AKR/J and C57L/J strains of mice

2000 ◽  
Vol 4 (1) ◽  
pp. 59-65 ◽  
Author(s):  
BEVERLY PAIGEN ◽  
NICHOLAS J. SCHORK ◽  
KAREN L. SVENSON ◽  
YIN-CHAI CHEAH ◽  
JIAN-LONG MU ◽  
...  
Keyword(s):  
Quantitative Trait ◽  
Congenic Strain ◽  
Cholesterol Gallstone ◽  
Gallstone Disease ◽  
Gallstone Formation ◽  
Quantitative Trait Loci Mapping ◽  
Cholesterol Gallstones ◽  
Lithogenic Diet ◽  
The Difference ◽  
Trait Locus

Quantitative trait locus (QTL) mapping was used to locate genes that determine the difference in cholesterol gallstone disease between the gallstone-susceptible strain C57L/J and the gallstone-resistant strain AKR/J. Gallstone weight was determined in 231 male (AKR × C57L) F1× AKR backcross mice fed a lithogenic diet containing 1% cholesterol, 0.5% cholic acid, and 15% butterfat for 8 wk. Mice having no stones and mice having the largest stones were genotyped at ∼20-cM intervals to find the loci determining cholesterol gallstone formation. The major locus, Lith1, mapped near D2Mit56 and was confirmed by constructing a congenic strain, AK.L- Lith1s. Another locus, Lith2, mapped near D19Mit58 and was also confirmed by constructing a congenic strain AK.L- Lith2s. Other suggestive, but not statistically significant, loci mapped to chromosomes 6, 7, 8, 10, and X. The identification of these Lith genes will elucidate the pathophysiology of cholesterol gallstone formation.

scholarly journals Liver-X-receptor-mediated increase in ATP-binding cassette transporter A1 expression is attenuated by fatty acids in CaCo- cells: effect on cholesterol efflux to high-density lipoprotein

2004 ◽  
Vol 377 (3) ◽  
pp. 545-552 ◽  
Author(s):  
Shubha MURTHY ◽  
Ella BORN ◽  
Satya N. MATHUR ◽  
F. Jeffrey FIELD
Keyword(s):  
Fatty Acids ◽  
Oleic Acid ◽  
Cholesterol Efflux ◽  
Atp Binding ◽  
Transcriptional Level ◽  
Mrna Levels ◽  
Atp Binding Cassette Transporter ◽  
Arachidonic Acids ◽  
Docosahexaenoic Acids ◽  
Atp Binding Cassette

The effect of fatty acids on LXR (liver X receptors)-mediated enhancement of ABCA1 (ATP-binding cassette transporter A1) expression and cholesterol efflux was investigated in human intestinal cells CaCo-2. LXR activation by T0901317 increased basolateral cholesterol efflux to lipoprotein particles isolated at a density of 1.21 g/ml or higher. Oleic and arachidonic acids attenuated the amount of cholesterol isolated from these particles. Stearic, linoleic and docosahexaenoic acids also decreased cholesterol efflux from basolateral membranes, with the polyunsaturated fatty acids being the most potent. Although oleic, arachidonic and docosahexaenoic acids modestly decreased ABCA1 mRNA levels in response to LXR activation, stearic and linoleic acids did not. Except for oleic acid, all fatty acids substantially attenuated an increase in ABCA1 mass secondary to LXR activation. Inhibiting acyl-CoA:cholesterol acyltransferase activity prevented the decrease in cholesterol efflux caused by oleic acid. Thus, in response to LXR activation, all fatty acids decreased the efflux of cholesterol from the basolateral membrane of CaCo-2 cells. Although modest suppression of ABCA1 gene expression by oleic, arachidonic and docosahexaenoic acids cannot be completely excluded as a mechanism, the predominant effect of fatty acids on ABCA1 expression and cholesterol efflux is at a post-transcriptional level.

Increased risk of cholesterol gallstone formation in subjects with apolipoprotein E4 genotype: Its relation to bile composition and crystalization

1998 ◽  
Vol 114 ◽  
pp. A547
Author(s):  
K.J. van Erpecum ◽  
P. Portincasa ◽  
E.R.M. Eckhardt ◽  
B.J.M. van de Heijning ◽  
A.K. Groen ◽  
...  
Keyword(s):  
Cholesterol Gallstone ◽  
Gallstone Formation ◽  
Bile Composition ◽  
Apolipoprotein E4 ◽  
Increased Risk

scholarly journals Tenofovir Disoproxil Fumarate Is a New Substrate of ATP-Binding Cassette Subfamily C Member 11

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Wisith Tun-Yhong ◽  
Chatchai Chinpaisal ◽  
Perayot Pamonsinlapatham ◽  
Sindchai Kaewkitichai
Keyword(s):  
Tenofovir Disoproxil Fumarate ◽  
Efflux Pump ◽  
Specific Inhibitor ◽  
Atp Binding ◽  
Cellular Transport ◽  
Intracellular Accumulation ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Vesicular Uptake ◽  
Atp Binding Cassette

ABSTRACT Tenofovir disoproxil fumarate (TDF), a nucleotide reverse transcriptase inhibitor, after conversion to tenofovir (TFV), is mainly eliminated by glomerular filtration and active tubular secretion. The major adverse effect of tenofovir is nephrotoxicity; however, the exact mechanism remains poorly understood. In this study, the ATP-binding cassette subfamily C member 11 (ABCC11; multidrug resistance protein 8 [MRP8]) transporter, which is abundant in proximal tubular cells, was demonstrated to act as an efflux transporter of tenofovir. Real-time PCR (RT-PCR) and indirect immunofluorescence assays were used to determine MRP8 overexpression in a continuous cell line. Tenofovir accumulations were assessed by cytotoxicity, cellular transport, and vesicular uptake assays. Substrate specificity was confirmed using MK-571, an MRP-specific inhibitor, and methotrexate, which served as a known substrate. Intracellular and intravesicular concentrations of tenofovir were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The 50% cytotoxic concentration (CC50) of TDF in MRP8-overexpressing cells was 4.78 times higher than that of parental cells. Transport assays also showed that the intracellular accumulation of tenofovir in MRP8-overexpressing cells was 55 times lower than that in parental cells and was partly reversed by MK-571. Similarly, an “inside-out” vesicular uptake assay, using Sf9 inverted membrane vesicles to allow measuring of accumulation of the substrates into the vesicles, demonstrated a higher intravesicular concentration of tenofovir in MRP8-overexpressing vesicles than in Sf9 insect control vesicles. These effects were effectively reversed by increasing concentrations of the specific inhibitor MK-571. In conclusion, tenofovir is a new substrate of the MRP8 transporter. An alteration in the activity of this efflux pump may increase the intracellular accumulation of tenofovir in proximal renal tubular cells.

scholarly journals Steroid Hormones Control Circadian Elovl3 Expression in Mouse Liver

Endocrinology ◽  
2008 ◽  
Vol 149 (6) ◽  
pp. 3158-3166 ◽  
Author(s):  
Annelie Brolinson ◽  
Stéphane Fourcade ◽  
Andreas Jakobsson ◽  
Aurora Pujol ◽  
Anders Jacobsson
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Steroid Hormones ◽  
Mouse Liver ◽  
Atp Binding ◽  
Mrna Levels ◽  
Male Mice ◽  
Brown Adipose ◽  
Long Chain ◽  
Atp Binding Cassette

The Elovl3 gene belongs to the Elovl gene family, which encodes for enzymes involved in the elongation of very long chain fatty acids. The recognized role for the enzyme is to control the elongation of saturated and monounsaturated fatty acids up to 24 carbons in length. Elovl3 was originally identified as a highly expressed gene in brown adipose tissue on cold exposure. Here we show that hepatic Elovl3 mRNA expression follows a distinct diurnal rhythm exclusively in mature male mice, with a sharp increase early in the morning Zeitgeber time (ZT) 20, peaks around ZT2, and is back to basal level at the end of the light period at ZT10. In female mice and sexually immature male mice, the Elovl3 expression was constantly low. Fasting and refeeding mice with chow or high-fat diet did not alter the Elovl3 mRNA levels. However, animals that were exclusively fed during the day for 9 d displayed an inverted expression profile. In addition, we show that Elovl3 expression is transcriptionally controlled and significantly induced by the exposure of the synthetic glucocorticoid dexamethasone. Taken together, these data suggest that Elovl3 expression in mouse liver is under strict diurnal control by circulating steroid hormones such as glucocorticoids and androgens. Finally, Elovl3 expression was found to be elevated in peroxisomal transporter ATP-binding cassette, subfamily D(ALD), member 2 ablated mice and suppressed in ATP-binding cassette subfamily D(ALD) member 2 overexpressing mice, implying a tight cross talk between very long chain fatty acid synthesis and peroxisomal fatty acid oxidation.

scholarly journals A mouse model of necrotic biliary pancreatitis induced by combining gallstone formation and ligation of the biliary-pancreatic duct

2017 ◽  
Author(s):  
Zuobiao Yuan ◽  
Junyuan Zheng ◽  
Zhu Mei ◽  
Guoyong Hu ◽  
Yue Zeng
Keyword(s):  
Mouse Model ◽  
Pancreatic Duct ◽  
Gallstone Formation ◽  
Diet Group ◽  
Control Group ◽  
Chow Diet ◽  
Sham Operation ◽  
Biliary Pancreatitis ◽  
High Fat ◽  
Lithogenic Diet

AbstractObjectiveThe aim of the present investigation is to develop a mouse model of biliary pancreatitis with characteristics of both gallstone formation and pancreatitis, mimicking the human etiology and pathphysiological character.DesignMale C57BL/6 mice were fed with chow, high fat/cholesterol and lithogenic diet for 12 weeks respectively. Laparotomy was done followed by ligation of pancreatic duct (PD), bile duct and pancreatic duct (BPD), or sham operation.ResultsLittle or no evidence of pancreatitis was observed in PD group of mice fed with chow or high fat/cholesterol diet, or in the tail of pancreata removed from animals fed with lithogenic diet. In the head of pancreas, pancreas damage was dramatically more severe in the lithogenic group. When bile reflux was blocked by BPD, pancreas damage markedly reduced to level of chow diet group. The lithogenic diet group also developed significantly more severe multi organ dysfunction syndrome (MODS) in the lung, kidney and liver. The severity of pancreatitis is associated with persistent high bile level of cholesterol and bile acid after obstruction of the biliary-pancreatic duct. Cholesterol crystal aggravated injury of pancreatic acinar cells caused by taurocholate. After obstruction of the biliary-pancreatic duct, in the lithogenic diet group, liver Abcg8 and Cyp7a1 was up-regulated, compared to the control group.ConclusionWe developed a mouse model of severe biliary pancreatitis in both local pancreas damage and MODS. This model provides a sound explanation for the Opie theory dilemma and a potential therapeutical direction in clinical practice as well.Summary statementA biliary pancreatitis has characters of both gallstone and pancreatitis, mimicking human etiology and pathophysiology, which gave a clear answer to the long time Opie theory dilemma.

scholarly journals Protective Effects of Yinchenhao Decoction on Cholesterol Gallstone in Mice Fed a Lithogenic Diet by Regulating LXR, CYP7A1, CYP7B1, and HMGCR Pathways

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Yong Meng ◽  
Ke Meng ◽  
Xin Zhao ◽  
Donghua Li ◽  
Qiaoying Gao ◽  
...  
Keyword(s):  
Cholesterol Gallstone ◽  
Saturation Index ◽  
Gallstone Formation ◽  
Intragastric Administration ◽  
Protective Effects ◽  
Biochemical Tests ◽  
Lithogenic Diet ◽  
Preventive Drug ◽  
Cholesterol Saturation Index ◽  
Bile Cholesterol

The study attempted to elucidate whether lipid genes are closely associated with lipid metabolic abnormalities during the lithogenic time and how Yinchenhao Decoction (YCHD) works on the transcriptions of lipid genes against cholesterol gallstone model. C57BL/6J mice fed on lithogenic diet (LD) were used for model establishment and randomized into 5 groups. All groups received LD for different weeks with isometrically intragastric administration of YCHD or NS. Biochemical tests were measured and liver tissues were harvested for histological and genetic detection. It was found that all groups with increasing LD showed a following tendency of gallstone incidence, bile cholesterol, phospholipids, total bile acid, and cholesterol saturation index (CSI). Conversely, YCHD could significantly normalize the levels of gallstone incidence, bile lipids, and CSI (CSI<1). As lithogenic time progressed, ABCG5, ABCG8, PPAR-α, and ABCB4 were upregulated, and SREBP2, CYP7A1, and CYP7B1 were downregulated, while CYP7A1, CYP7B1, LXR, and HMGCR mRNA were increased 3-fold under the administration of YCHD. It was concluded that abnormal expressions of the mentioned genes may eventually progress to cholesterol gallstone. CYP7A1, CYP7B1, LXR, and HMGCR mRNA may be efficient targets of YCHD, which may be a preventive drug to reverse liver injury, normalize bile lipids, facilitate gallstone dissolution, and attenuate gallstone formation.

Sign in / Sign up

Export Citation Format

Share Document