Targeting the alternative bile acid synthetic pathway for metabolic diseases
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Protein & Cell
REVIEW Targeting the alternative bile acid synthetic pathway for metabolic diseases Wei Jia1,2&
1
3
, Meilin Wei , Cynthia Rajani , Xiaojiao Zheng
1&
Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China 2 School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China 3 University of Hawaii Cancer Center, Honolulu, HI 96813, USA & Correspondence: [email protected] (W. Jia), [email protected] (X. Zheng) Received July 7, 2020 Accepted October 21, 2020
ABSTRACT 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.
KEYWORDS bile acids, gut microbiota, alternative pathway, metabolic diseases
© The Author(s) 2020
INTRODUCTION The gut microbiota and the host co-metabolize a vast array of small molecule metabolites, many of which play critical roles in shuttling information between the eukaryotic and prokaryotic cells. Many of these small molecule metabolites, such as bile acids (BAs), short-chain fatty acids (SCFAs), and neurotransmitters, are produced and circulated in the gastrointestinal system as well as systemically, and are associated with diverse metabolic disorders including type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD) (Nicholson et al., 2012; Arora and Bäckhed, 2016; Jia et al., 2018). One example is the contribution of the gut microbiota to the development of chronic liver disease, such as NAFLD, through multiple mechanisms, including increased production of lipopolysaccharides (LPS), inflam
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