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

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Modulation of intrahepatic cholesterol trafficking: evidence by in vivo antisense treatment for the involvement of sterol carrier protein-2 in newly synthesized cholesterol transport into rat bile

Biochemical Journal ◽

10.1042/bj3170681 ◽

1996 ◽

Vol 317 (3) ◽

pp. 681-687 ◽

Cited By ~ 45

Author(s):

Luigi PUGLIELLI ◽

Attilio RIGOTTI ◽

Ludwig AMIGO ◽

Liliana NUÑEZ ◽

Aldo V. GRECO ◽

...

Keyword(s):

Time Course ◽

Molecular Mechanisms ◽

Cholesterol Gallstone ◽

The Body ◽

Biliary Secretion ◽

Carrier Protein ◽

Sterol Carrier Protein ◽

Biliary Cholesterol ◽

Sterol Carrier Protein 2

Biliary cholesterol represents one of the two major excretory pathways for sterol elimination from the body and plays a central role in cholesterol gallstone formation. Biliary cholesterol originates from a precursor pool of preformed and newly synthesized free cholesterol. Although it has been suggested that newly synthesized and preformed biliary cholesterol are secreted by independent pathways, the specific cellular and molecular mechanisms are unknown. We used male Wistar rats to study the time-course of the appearance of newly synthesized cholesterol, phosphatidylcholine and protein into bile. The specific role of sterol carrier protein-2 (SCP-2) in the transport of newly synthesized biliary cholesterol was evaluated by an in vivo antisense oligonucleotide approach. In contrast to [14C]phosphatidylcholine and [35S]proteins, the time-course of [14C]cholesterol appearance into bile was rapid, and microtubule- and Golgi-independent. In vivo SCP-2 antisense treatment reduced and delayed the appearance of biliary [14C]cholesterol. Furthermore, hepatic SCP-2 expression increased more than 3-fold over control values in rats that had been treated with diosgenin to increase biliary secretion of newly synthesized cholesterol. These results suggest that SCP-2 is necessary for the rapid transport of newly synthesized cholesterol into bile and that hepatocytes can induce SCP-2 expression according to the rate of biliary secretion of newly synthesized cholesterol.

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Studies with sterol carrier protein 2 (SCP2) gene knockout mice identify liver fatty acid binding protein (FABP1) as intracellular cholesterol transporter contributing to biliary cholesterol hypersecretion and gallstone formation

Gastroenterology ◽

10.1016/s0016-5085(00)85843-6 ◽

2000 ◽

Vol 118 (4) ◽

pp. A926 ◽

Cited By ~ 8

Author(s):

Andrea Hafer ◽

Nadine Katzberg ◽

Christian Muench ◽

Juergen Scheibner ◽

Eduard Friedrich Stange ◽

...

Keyword(s):

Fatty Acid Binding Protein ◽

Gene Knockout ◽

Gallstone Formation ◽

Sterol Carrier Protein ◽

Liver Fatty Acid ◽

Biliary Cholesterol ◽

Fatty Acid Binding ◽

Acid Binding Protein ◽

Gene Knockout Mice ◽

Sterol Carrier Protein 2

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

Digestive Diseases ◽

10.1159/000465517 ◽

2017 ◽

Vol 35 (5) ◽

pp. 439-443 ◽

Cited By ~ 1

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.

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