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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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Tissue distribution of CIC and ATXN1L proteins in mice.Western blot analysis for tissue distribution of CIC and ATXN1L proteins at P18. Twenty μg of total protein extract was loaded on each lane. KO means Cic-L-/- mouse.
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f1: Tissue distribution of CIC and ATXN1L proteins in mice.Western blot analysis for tissue distribution of CIC and ATXN1L proteins at P18. Twenty μg of total protein extract was loaded on each lane. KO means Cic-L-/- mouse.

Mentions: To get insight of in vivo physiological roles of CIC, we first checked tissue distribution of CIC and ATXN1L proteins in mice. We found that CIC was expressed in various types of tissues, except for kidney (Fig. 1), and that ATXN1L levels decreased in all tested Cic-L-/- tissues (Fig. 1), suggesting that CIC exists as a complex with ATXN1L in most tissues. Next, we investigated whether Cic-L-/- mice had metabolic abnormalities by measuring the levels of serum metabolites in WT and Cic-L-/- mice at P18, and found that glucose levels were decreased whereas levels of BA and total bilirubin were significantly increased in sera from Cic-L-/- mice compared with WT (Table 1). It is also noteworthy that the serum alanine transaminase (ALT) level, a general parameter indicating liver insult, was increased in Cic-L-/- mice, though not statistically significant (Table 1), suggesting that Cic-L-/- mice might have defects in liver function.


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)

Tissue distribution of CIC and ATXN1L proteins in mice.Western blot analysis for tissue distribution of CIC and ATXN1L proteins at P18. Twenty μg of total protein extract was loaded on each lane. KO means Cic-L-/- mouse.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317698&req=5

f1: Tissue distribution of CIC and ATXN1L proteins in mice.Western blot analysis for tissue distribution of CIC and ATXN1L proteins at P18. Twenty μg of total protein extract was loaded on each lane. KO means Cic-L-/- mouse.
Mentions: To get insight of in vivo physiological roles of CIC, we first checked tissue distribution of CIC and ATXN1L proteins in mice. We found that CIC was expressed in various types of tissues, except for kidney (Fig. 1), and that ATXN1L levels decreased in all tested Cic-L-/- tissues (Fig. 1), suggesting that CIC exists as a complex with ATXN1L in most tissues. Next, we investigated whether Cic-L-/- mice had metabolic abnormalities by measuring the levels of serum metabolites in WT and Cic-L-/- mice at P18, and found that glucose levels were decreased whereas levels of BA and total bilirubin were significantly increased in sera from Cic-L-/- mice compared with WT (Table 1). It is also noteworthy that the serum alanine transaminase (ALT) level, a general parameter indicating liver insult, was increased in Cic-L-/- mice, though not statistically significant (Table 1), suggesting that Cic-L-/- mice might have defects in liver function.

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