Improving glucose and lipids metabolism: drug development based on bile acid related targets

Abstract

Bariatric surgery is one of the most effective treatment options for severe obesity and its comorbidities. However, it is a major surgery that poses several side effects and risks which impede its clinical use. Therefore, it is urgent to develop alternative safer pharmacological approaches to mimic bariatric surgery. Recent studies suggest that bile acids are key players in mediating the metabolic benefits of bariatric surgery. Bile acids can function as signaling molecules by targeting bile acid nuclear receptors and membrane receptors, like FXR and TGR5 respectively. In addition, the composition of bile acids is regulated by either the hepatic sterol enzymes such as CYP8B1 or the gut microbiome. These bile acid related targets all play important roles in regulating metabolism. Drug development based on these targets could provide new hope for patients without the risks of surgery and at a lower cost. In this review, we summarize the most updated progress on bile acid related targets and development of small molecules as drug candidates based on these targets.

Quinoa Reduces High-Fat Diet-Induced Obesity in Mice via Potential Microbiota-Gut-Brain-Liver Interaction Mechanisms

“…GLP-1, mainly produced in gut endocrine cells and in the brain, is a peptide that involves in regulating gut motility, satiety, and glucose metabolism ( 25 ). GLP-1 is released after food intake and acts to amplify glucose-dependent insulin secretion, and it has been in the spotlight as a target for the treatment of obesity and diabetes as its positive effects on glucose homeostasis, appetite regulation, gastric emptying and postprandial lipid metabolism ( 26 , 27 ). In addition to TGR5, short-chain fatty acids (SCFAs), metabolites of intestinal microbiota, can promote GLP-1 secretion from L cells and improve glucose tolerance ( 28 ).…”

Shifts in gut microbiota and their metabolites induced by bariatric surgery. Impact of factors shaping gut microbiota on bariatric surgery outcomes

“…TGR5 is mainly activated by secondary bile acids, being lithocholic acid and taurolithocholic acid the most potent endogenous agonist. TGR5 activation increases energy expenditure and stimulates insulin secretion [62].…”

Gut microbiome-derived hydrolases—an underrated target of natural product metabolism

“…As illustrated in Figure 3 , BSH primarily catalyzes the hydrolysis of endogenous steroidal natural product BAs, releasing bound BAs in the intestinal bile acid pool into free bile acids and amino acid residues ( Rimal et al., 2024 ). Numerous studies have highlighted the significance of BSH-mediated unbinding in BAs metabolism, impacting cholesterol synthesis, lipid metabolism, and glucose metabolism ( Shen et al., 2021 ; Zhu et al., 2022 ). Recent research has also revealed that BSH enzymes are involved in degrading antibiotics, in addition to their role in BAs unbinding.…”