Our digestive system converts food into their simplest forms, like glucose (building blocks for sugars), amino acids (building blocks for proteins) or fatty acids (that building blocks for fats). Foods are first broken down by the stomach, and then absorbed by the small intestine, which distributes the nutrients throughout the body via the bloodstream. There are many players that help in the digestion/breakdown of food into simpler forms. One key player involved is bile acid, which is produced by the liver and stored in the gallbladder. After ingestion of food, bile acid flows into a section of the stomach called the duodenum, where it plays an especially important role in breaking down fats and fat-soluble vitamins. Bile acid is then re-absorbed from the stomach and transported back to the liver. This entire process is called enterohepatic circulation of bile acid. When the body fails to control the production and excretion of the potent bile acid, it can cause liver damage, induction of inflammatory response, and cholestasis -- a decrease in bile flow due to impaired secretion by the liver.

Capicua (CIC), as discussed extensively by the past articles of this digest, has been implicated to play roles in diseases, such as Spinocerebellar ataxia type 1 (SCA1), certain forms of cancer (T-ALL), and even in neurological behavioural phenotypes. However, up until this article was published, few people had explored CIC’s physiological role in the many organs of the body. Thus, these researchers sought to explore how the body reacted when they essentially prevented the production of sufficient levels of CIC in mice. They observed that a disruption of CIC levels caused intriguing metabolic abnormalities in the digestive systems of these CIC deficient mice, compared to their normal counterparts. They found that glucose levels were decreased whereas levels of bile acid in the digestive system were significantly increased. These metabolic abnormalities led the researchers to focus on the liver, as it plays many roles in controlling the body’s metabolism.

The researchers observed that, upon removing CIC in the liver, the levels of several genes that modify and remove bile acids from liver cells were altered. This observation, paired with the metabolic abnormalities in these mice, led the researchers to hypothesize that regulation and control of bile acid levels were affected by insufficient levels of CIC.

To test this hypothesis, the authors first looked at the gallbladder, which is where bile acid is stored, to see if there were any defects. Indeed, mice with insufficient CIC levels had shrunken gallbladders compared to their normal counterparts. Meanwhile, by comparing the levels of bile acid between CIC deficient mice and normal mice, they found that mutant mice failed to circulate bile acid between the intestine and the liver. The researchers further showed that these defects were due to reduced levels of genes involved in bile acid synthesis in the CIC deficient mice, and they identified the bile acid transporter genes that seemed to be affected most by CIC deficiency. These abnormalities in bile acid homeostasis culminated in inflammation of the liver and cholestasis.

Overall, these results demonstrate that CIC plays a critical role in controlling bile acid homeostasis. This study provides new insight into the role of CIC in normal liver function and metabolism, and raises the possibility that CIC dysfunction might be associated with pathogenesis of chronic liver disease and metabolic disorders in humans.

Reference:

Kim, E. et al. Deficiency of Capicua disrupts bile acid homeostasis. Sci Rep 5, 8272 (2015). Link to the full text article.