Targeting the alternative bile acid synthetic pathway for metabolic diseases

Wei Jia*, Meilin Wei, Cynthia Rajani, Xiaojiao Zheng*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

158 Citations (Scopus)


The gut microbiota is profoundly involved in glucose and lipid metabolism, in part by regulating bile acid (BA) metabolism and affecting multiple BA-receptor signaling pathways. BAs are synthesized in the liver by multi-step reactions catalyzed via two distinct routes, the classical pathway (producing the 12α-hydroxylated primary BA, cholic acid), and the alternative pathway (producing the non-12α-hydroxylated primary BA, chenodeoxycholic acid). BA synthesis and excretion is a major pathway of cholesterol and lipid catabolism, and thus, is implicated in a variety of metabolic diseases including obesity, insulin resistance, and nonalcoholic fatty liver disease. Additionally, both oxysterols and BAs function as signaling molecules that activate multiple nuclear and membrane receptor-mediated signaling pathways in various tissues, regulating glucose, lipid homeostasis, inflammation, and energy expenditure. Modulating BA synthesis and composition to regulate BA signaling is an interesting and novel direction for developing therapies for metabolic disease. In this review, we summarize the most recent findings on the role of BA synthetic pathways, with a focus on the role of the alternative pathway, which has been under-investigated, in treating hyperglycemia and fatty liver disease. We also discuss future perspectives to develop promising pharmacological strategies targeting the alternative BA synthetic pathway for the treatment of metabolic diseases.

Original languageEnglish
Pages (from-to)411-425
Number of pages15
JournalProtein and Cell
Issue number5
Early online date30 Nov 2020
Publication statusPublished - May 2021

Scopus Subject Areas

  • Biotechnology
  • Biochemistry
  • Drug Discovery
  • Cell Biology

User-Defined Keywords

  • alternative pathway
  • bile acids
  • gut microbiota
  • metabolic diseases


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