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Deficiency of Capicua disrupts bile acid homeostasis.

Kim E, Park S, Choi N, Lee J, Yoe J, Kim S, Jung HY, Kim KT, Kang H, Fryer JD, Zoghbi HY, Hwang D, Lee Y - Sci Rep (2015)

Bottom Line: We also found that levels of proinflammatory cytokine genes were up-regulated in Cic-L(-/-) liver.Moreover, induction of tumor necrosis factor alpha (Tnfα) expression and decrease in the levels of FOXA2, C/EBPβ, and RXRα were found in Cic-L(-/-) liver before BA was accumulated, suggesting that inflammation might be the cause for the cholestasis in Cic-L(-/-) mice.Our findings indicate that CIC is a critical regulator of BA homeostasis, and that its dysfunction might be associated with chronic liver disease and metabolic disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Republic of Korea.

ABSTRACT
Capicua (CIC) has been implicated in pathogenesis of spinocerebellar ataxia type 1 and cancer in mammals; however, the in vivo physiological functions of CIC remain largely unknown. Here we show that Cic hypomorphic (Cic-L(-/-)) mice have impaired bile acid (BA) homeostasis associated with induction of proinflammatory cytokines. We discovered that several drug metabolism and BA transporter genes were down-regulated in Cic-L(-/-) liver, and that BA was increased in the liver and serum whereas bile was decreased within the gallbladder of Cic-L(-/-) mice. We also found that levels of proinflammatory cytokine genes were up-regulated in Cic-L(-/-) liver. Consistent with this finding, levels of hepatic transcriptional regulators, such as hepatic nuclear factor 1 alpha (HNF1α), CCAAT/enhancer-binding protein beta (C/EBPβ), forkhead box protein A2 (FOXA2), and retinoid X receptor alpha (RXRα), were markedly decreased in Cic-L(-/-) mice. Moreover, induction of tumor necrosis factor alpha (Tnfα) expression and decrease in the levels of FOXA2, C/EBPβ, and RXRα were found in Cic-L(-/-) liver before BA was accumulated, suggesting that inflammation might be the cause for the cholestasis in Cic-L(-/-) mice. Our findings indicate that CIC is a critical regulator of BA homeostasis, and that its dysfunction might be associated with chronic liver disease and metabolic disorders.

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Impaired BA homeostasis in Cic-L-/- mice.(a) Pictures showing the size of gallbladders in WT and Cic-L-/- mice at P18. GB, L, and I mean gallbladder, liver, and intestine, respectively. Arrows indicate the gallbladder. (b) Hepatic and small intestinal BA levels and total BA pool size in WT and Cic-L-/- mice (n = 4~7 per each genotype) at P18. ***P<0.001. All error bars show s.e.m. (c) qRT-PCR analysis for levels of Shp and key genes involved in BA biosynthesis and transport in livers from 18 day-old WT and Cic-L-/- mice (n = 4~9 per each genotype). #P = 0.054, **P<0.01 and ***P<0.001. All error bars show s.e.m. (d) qRT-PCR analysis for levels of membrane transporter genes in livers from 18 day-old WT and Cic-L-/- mice (n = 3~6 per each genotype). *P<0.05, **P<0.01 and ***P<0.001. All error bars show s.e.m.
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f3: Impaired BA homeostasis in Cic-L-/- mice.(a) Pictures showing the size of gallbladders in WT and Cic-L-/- mice at P18. GB, L, and I mean gallbladder, liver, and intestine, respectively. Arrows indicate the gallbladder. (b) Hepatic and small intestinal BA levels and total BA pool size in WT and Cic-L-/- mice (n = 4~7 per each genotype) at P18. ***P<0.001. All error bars show s.e.m. (c) qRT-PCR analysis for levels of Shp and key genes involved in BA biosynthesis and transport in livers from 18 day-old WT and Cic-L-/- mice (n = 4~9 per each genotype). #P = 0.054, **P<0.01 and ***P<0.001. All error bars show s.e.m. (d) qRT-PCR analysis for levels of membrane transporter genes in livers from 18 day-old WT and Cic-L-/- mice (n = 3~6 per each genotype). *P<0.05, **P<0.01 and ***P<0.001. All error bars show s.e.m.

Mentions: Given that BA levels were significantly increased in sera from Cic-L-/- mice (Table 1), and that some of the drug metabolism genes down-regulated in Cic-L-/- liver, Cyp2b10, Gstm2, and Sult2a1, are known to be involved in detoxification and excretion of BAs1819, we hypothesized that BA homeostasis might be dysregulated in Cic-L-/- mice. To test this hypothesis, we first checked bile content within gallbladders of 18 day-old WT and Cic-L-/- mice after overnight fasting. Surprisingly, Cic-L-/- mice showed dramatically shrunken gallbladders (Figs. 3a and S1), indicating that they have less bile within the gallbladder in comparison with WT. We next measured the concentration of hepatic and intestinal BAs as well as total BA pool sizes in WT and Cic-L-/- mice. A significant increase in hepatic BA levels was found in Cic-L-/- mice while total BA pool size was comparable between them (Fig. 3b). These data suggest that CIC deficiency impairs the enterohepatic circulation of BA, based on our finding showing accumulation of BAs in serum and liver and dilatory excretion of bile into gallbladder in Cic-L-/- mice.


Deficiency of Capicua disrupts bile acid homeostasis.

Kim E, Park S, Choi N, Lee J, Yoe J, Kim S, Jung HY, Kim KT, Kang H, Fryer JD, Zoghbi HY, Hwang D, Lee Y - Sci Rep (2015)

Impaired BA homeostasis in Cic-L-/- mice.(a) Pictures showing the size of gallbladders in WT and Cic-L-/- mice at P18. GB, L, and I mean gallbladder, liver, and intestine, respectively. Arrows indicate the gallbladder. (b) Hepatic and small intestinal BA levels and total BA pool size in WT and Cic-L-/- mice (n = 4~7 per each genotype) at P18. ***P<0.001. All error bars show s.e.m. (c) qRT-PCR analysis for levels of Shp and key genes involved in BA biosynthesis and transport in livers from 18 day-old WT and Cic-L-/- mice (n = 4~9 per each genotype). #P = 0.054, **P<0.01 and ***P<0.001. All error bars show s.e.m. (d) qRT-PCR analysis for levels of membrane transporter genes in livers from 18 day-old WT and Cic-L-/- mice (n = 3~6 per each genotype). *P<0.05, **P<0.01 and ***P<0.001. All error bars show s.e.m.
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Related In: Results  -  Collection

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f3: Impaired BA homeostasis in Cic-L-/- mice.(a) Pictures showing the size of gallbladders in WT and Cic-L-/- mice at P18. GB, L, and I mean gallbladder, liver, and intestine, respectively. Arrows indicate the gallbladder. (b) Hepatic and small intestinal BA levels and total BA pool size in WT and Cic-L-/- mice (n = 4~7 per each genotype) at P18. ***P<0.001. All error bars show s.e.m. (c) qRT-PCR analysis for levels of Shp and key genes involved in BA biosynthesis and transport in livers from 18 day-old WT and Cic-L-/- mice (n = 4~9 per each genotype). #P = 0.054, **P<0.01 and ***P<0.001. All error bars show s.e.m. (d) qRT-PCR analysis for levels of membrane transporter genes in livers from 18 day-old WT and Cic-L-/- mice (n = 3~6 per each genotype). *P<0.05, **P<0.01 and ***P<0.001. All error bars show s.e.m.
Mentions: Given that BA levels were significantly increased in sera from Cic-L-/- mice (Table 1), and that some of the drug metabolism genes down-regulated in Cic-L-/- liver, Cyp2b10, Gstm2, and Sult2a1, are known to be involved in detoxification and excretion of BAs1819, we hypothesized that BA homeostasis might be dysregulated in Cic-L-/- mice. To test this hypothesis, we first checked bile content within gallbladders of 18 day-old WT and Cic-L-/- mice after overnight fasting. Surprisingly, Cic-L-/- mice showed dramatically shrunken gallbladders (Figs. 3a and S1), indicating that they have less bile within the gallbladder in comparison with WT. We next measured the concentration of hepatic and intestinal BAs as well as total BA pool sizes in WT and Cic-L-/- mice. A significant increase in hepatic BA levels was found in Cic-L-/- mice while total BA pool size was comparable between them (Fig. 3b). These data suggest that CIC deficiency impairs the enterohepatic circulation of BA, based on our finding showing accumulation of BAs in serum and liver and dilatory excretion of bile into gallbladder in Cic-L-/- mice.

Bottom Line: We also found that levels of proinflammatory cytokine genes were up-regulated in Cic-L(-/-) liver.Moreover, induction of tumor necrosis factor alpha (Tnfα) expression and decrease in the levels of FOXA2, C/EBPβ, and RXRα were found in Cic-L(-/-) liver before BA was accumulated, suggesting that inflammation might be the cause for the cholestasis in Cic-L(-/-) mice.Our findings indicate that CIC is a critical regulator of BA homeostasis, and that its dysfunction might be associated with chronic liver disease and metabolic disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, Republic of Korea.

ABSTRACT
Capicua (CIC) has been implicated in pathogenesis of spinocerebellar ataxia type 1 and cancer in mammals; however, the in vivo physiological functions of CIC remain largely unknown. Here we show that Cic hypomorphic (Cic-L(-/-)) mice have impaired bile acid (BA) homeostasis associated with induction of proinflammatory cytokines. We discovered that several drug metabolism and BA transporter genes were down-regulated in Cic-L(-/-) liver, and that BA was increased in the liver and serum whereas bile was decreased within the gallbladder of Cic-L(-/-) mice. We also found that levels of proinflammatory cytokine genes were up-regulated in Cic-L(-/-) liver. Consistent with this finding, levels of hepatic transcriptional regulators, such as hepatic nuclear factor 1 alpha (HNF1α), CCAAT/enhancer-binding protein beta (C/EBPβ), forkhead box protein A2 (FOXA2), and retinoid X receptor alpha (RXRα), were markedly decreased in Cic-L(-/-) mice. Moreover, induction of tumor necrosis factor alpha (Tnfα) expression and decrease in the levels of FOXA2, C/EBPβ, and RXRα were found in Cic-L(-/-) liver before BA was accumulated, suggesting that inflammation might be the cause for the cholestasis in Cic-L(-/-) mice. Our findings indicate that CIC is a critical regulator of BA homeostasis, and that its dysfunction might be associated with chronic liver disease and metabolic disorders.

Show MeSH
Related in: MedlinePlus