Deficiency of Capicua disrupts bile acid homeostasis

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.

Capicua suppresses hepatocellular carcinoma progression by controlling the ETV4–MMP1 axis

“…Knockdown of CIC did not increase levels of PEA3 group genes in HepG2 cells (Fig. C), suggesting that CIC differentially regulates its target gene expression in a cell type–dependent manner, which is consistent with previous findings . Furthermore, the up‐regulation of ETV4 expression in CIC knockdown HCC cells was confirmed at the protein level (Fig.…”

“…In mammals, CIC has been implicated in the pathogenesis of spinocerebellar ataxia type 1 neurodegenerative disease, as well as regulation of essential processes such as lung alveolarization, liver homeostasis, learning and memory, and follicular helper T‐cell differentiation . CIC has also been studied in several cancer contexts, and mutations of it have been found in soft tissue, brain, lung, gastric, prostate, and breast cancers .…”

“…(17) In Drosophila, several studies revealed that Cic regulates not only anteroposterior and dorsoventral body patterning but also intestinal stem cell proliferation, (22) wing development, (23) and other processes in development. (24) In mammals, CIC has been implicated in the pathogenesis of spinocerebellar ataxia type 1 neurodegenerative disease, (25) as well as regulation of essential processes such as lung alveolarization, (26) liver homeostasis, (27) learning and memory, (28) and follicular helper T-cell differentiation. (29) CIC has also been studied in several cancer contexts, and mutations of it have been found in soft tissue, brain, lung, gastric, prostate, and breast cancers.…”

A double‐edged sword: The world according to Capicua in cancer

“…In human, the germline heterozygous CIC truncating mutations were reported in patients of intellectual disability, attention deficit hyperactivity disorder, and autism spectrum disorder . The Cic‐L knockout homozygous mutant also shows downregulation of transporter genes such as Bsep and Mdr2 in hepatocytes showing bile acid accumulation . CIC is ubiquitously expressed in many organs except for kidney, and thus its function is important for homeostasis of multiple organs.…”

“…(26) The Cic-L knockout homozygous mutant also shows downregulation of transporter genes such as Bsep and Mdr2 in hepatocytes showing bile acid accumulation. (27) CIC is ubiquitously expressed in many organs except for kidney, and thus its function is important for homeostasis of multiple organs.…”