FXR as a Drug Target to Treat Progressive Familial Intrahepatic Cholestasis

Ivy, Kathryn Stevens
March 2015
Vanderbilt Undergraduate Research Journal;Spring2015, Vol. 10, p1
Academic Journal
Progressive Familial Intrahepatic Cholestasis (PFIC) is a condition that results in the cirrhosis of the liver and eventually liver failure due to impaired bile flow. If left untreated and even if treated, PFIC will result usually in an early death. While the causes of this disease vary, all types present with a similar symptoms and eventual prognosis. There are four main proposed subtypes of intrahepatic cholestasis: disorders of membrane transport and secretion, disorders of bile acid biosynthesis and conjugation, disorders of embryogenesis and lastly, an unclassified group. The careful maintenance of bile salt homeostasis is crucial to the metabolism of fats and normal liver function. These genes are involved with the regulation and transport of bile from hepatocytes into the gallbladder and eventually to the ileum of the small intestines. Because maintenance of symptoms can be regulated to improve longevity and quality of life, it is important to further elucidate the mechanisms that lead to cholestasis. By understanding these mechanisms we can hope to develop treatments that target specifically the precursors and downstream effectors in the previously indicated genes. With early detection of PFIC, there is an opportunity for therapy, however the current pharmacologic opportunities are few and have a low efficacy. Therefore there is much need for a stronger and more selective treatment that can be directed to the cause of PFIC instead of its symptoms. I postulate that FXR is a good target because of its advantageous position as a transcription factor.


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