Recent advances in the development of farnesoid X receptor agonists

Ahmad H. Ali, Elizabeth J. Carey, Keith Lindor

Research output: Contribution to journalReview article

118 Citations (Scopus)

Abstract

Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing.

Original languageEnglish (US)
Article number5
JournalAnnals of Translational Medicine
Volume3
Issue number1
DOIs
StatePublished - Jan 1 2015

Fingerprint

Bile Acids and Salts
Chenodeoxycholic Acid
Insulin Resistance
Biliary Liver Cirrhosis
Wounds and Injuries
Clinical Trials
Cholesterol 7-alpha-Hydroxylase
Phase II Clinical Trials
Liver Regeneration
Glucose Intolerance
Liver
Cholestasis
Carbohydrate Metabolism
Fatty Liver
Cytoplasmic and Nuclear Receptors
Hyperlipidemias
Lipid Metabolism
Bilirubin
Liver Cirrhosis
Type 2 Diabetes Mellitus

Keywords

  • Farnesoid X receptor (FXR)
  • Nonalcoholic fatty liver disease (NAFLD)
  • Obeticholic acid (OCA)
  • Primary biliary cirrhosis (PBC)
  • Primary sclerosing cholangitis (PSC)

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Recent advances in the development of farnesoid X receptor agonists. / Ali, Ahmad H.; Carey, Elizabeth J.; Lindor, Keith.

In: Annals of Translational Medicine, Vol. 3, No. 1, 5, 01.01.2015.

Research output: Contribution to journalReview article

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