Abstract
Bile acids are derived from cholesterol to facilitate intestinal nutrient absorption and biliary secretion of cholesterol. Recent studies have identified bile acids as signaling molecules that activate nuclear farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor-1 (Gpbar-1, also known as TGR5) to maintain metabolic homeostasis and protect liver and other tissues and cells from bile acid toxicity. Bile acid homeostasis is regulated by a complex mechanism of feedback and feedforward regulation that is not completely understood. This review will cover recent advances in bile acid signaling and emerging concepts about the classic and alternative bile acid synthesis pathway, bile acid composition and bile acid pool size, and intestinal bile acid signaling and gut microbiome in regulation of bile acid homeostasis.
Highlights
Bile acid synthesis is tightly regulated by a network of feedback mechanisms that is complex and not completely understood
Recent research using mouse genetic models and human patients has shown that bile acids are signaling molecules that activate nuclear farnesoid X receptor (FXR), membrane G protein-coupled bile acid receptor-1 (Gpbar-1, known as Takeda G proteincoupled receptor 5, or Takeda G protein receptor 5 (TGR5)), and sphingosine-1-phosphate receptor 2 (S1PR2) to regulate bile acid synthesis in the liver and lipid, glucose, and energy metabolism in tissues, including the liver, intestine, macrophages, and adipose tissues
This review will briefly discuss recent advances in understanding how bile acid homeostasis is maintained by (1) the classic bile acid synthesis pathway versus the alternative bile acid synthesis pathway, (2) regulation of bile acid pool size versus composition, (3) FXR signaling in liver versus intestine, and (4) the gut microbiota-to-liver axis
Summary
Bile acid synthesis is tightly regulated by a network of feedback mechanisms that is complex and not completely understood. The classic pathway of bile acid synthesis is initiated by the ratelimiting enzyme cholesterol 7α-hydroxylase (CYP7A1) to form 7α-hydroxycholesterol, which is converted to 7α-hydroxy4-cholesten-3-one (named C4). In mouse and human liver, cholesterol 25-hydroxylase (CH25H, not a CYP enzyme) converts cholesterol to 25-hydroxycholesterol, which is the most abundant oxysterol in serum and can be used for synthesis bile acids in the liver. In Cyp7a1−/− mice, the alternative pathway is stimulated to produce bile acids to maintain a smaller but more hydrophilic bile acid pool with reduced tauro-cholic acid (TCA) and increased T-MCAs and taurodeoxycholic acid[4]. In Cyp7a1−/− mice, bile acid synthesis is switched to the alternative pathway to produce less TCA but more T-αMCA and T-βMCA, which antagonizes intestinal FXR activity to reduce ceramide synthesis and increase insulin sensitivity. Bile acid composition, rather than bile acid pool size, plays an important role in regulation of bile acid and cholesterol homeostasis and protects against DIO and insulin resistance
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