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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.

SUBMITTER: Shen H

PROVIDER: S-EPMC7784708 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Shen Hanchen H Ding Lili L Baig Mehdi M Tian Jingyan J Wang Yang Y Huang Wendong W

Cell stress 20210105 1

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 aci ...[more]

PMID: 33447732

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Project description:Bile acid (BA) biotransformation by gut bacteria impacts BA profile and signaling to nuclear receptors, such as the farnesoid X receptor (FXR) regulating glucose metabolism. Altered BA-FXR signaling was therefore investigated as a potential mechanism linking polyphenol-induced gut bacterial changes and improved glucose metabolism. Diabetic db/db were fed low-fat diet (LFD) or LFD supplemented with a proanthocyanidin-rich extract of grape polyphenols (LFD-GP) for 4 weeks. Metabolic phenotypes, serum BAs, gut microbiota composition, and gene expression markers relevant to gut barrier and glucose metabolism were assessed. Gut organoids were used to investigate effects of individual BAs on ileal FXR activity. Compared with LFD-fed controls, GP supplemented db/db mice showed improved glucose metabolism, decreased relative abundance of gut bacteria associated with production of secondary BAs (SBAs), and depleted serum levels of SBAs taurohyodeoxycholic acid (THDCA), ω-muricholic acid (ωMCA), and tauro-ω-muricholic acid (TωMCA). Serum levels of primary BAs (PBAs) increased, consistent with higher gene expression of PBA synthesis enzyme Cyp7a1. GP-induced BA changes associated with FXR inhibition as evidenced by reduced expression of FXR-responsive genes Shp, Fgf15, and Fabp6 in ileum tissue as well as hepatic Shp, which negatively regulates PBA synthesis. GP treatment did not affect expression of hepatic Fxr or expression of Abcb11, Slc51b, and Obp2a genes controlling BA transport. Ceramide biosynthesis genes Smpd3, Sptlc2, and Cers4 were decreased in liver and intestine suggesting lower tissue ceramides levels may contribute to improved glucose metabolism. THDCA, ωMCA, and TωMCA behaved as FXR agonists in ileal organoid experiments; therefore, their depletion in serum of GP-supplemented db/db and wild type (WT) mice was consistent with FXR inhibition. These data suggest that by altering the gut microbiota, GPs modify BA-FXR signaling pathways to promote glucoregulation.

Project description:Drug-induced liver injury (DILI) is a matter of concern in the course of drug development and patient safety, often leading to discontinuation of drug-development programs or early withdrawal of drugs from market. Hepatocellular toxicity or impairment of bile acid (BA) metabolism, known as cholestasis, are the two clinical forms of DILI. Whole-body physiology-based modelling allows a mechanistic investigation of the physiological processes leading to cholestasis in man. Objectives of the present study were: (1) the development of a physiology-based model of the human BA metabolism, (2) population-based model validation and characterisation, and (3) the prediction and quantification of altered BA levels in special genotype subgroups and after drug administration. The developed physiology-based bile acid (PBBA) model describes the systemic BA circulation in humans and includes mechanistically relevant active and passive processes such as the hepatic synthesis, gallbladder emptying, transition through the gastrointestinal tract, reabsorption into the liver, distribution within the whole body, and excretion via urine and faeces. The kinetics of active processes were determined for the exemplary BA glycochenodeoxycholic acid (GCDCA) based on blood plasma concentration-time profiles. The robustness of our PBBA model was verified with population simulations of healthy individuals. In addition to plasma levels, the possibility to estimate BA concentrations in relevant tissues like the intracellular space of the liver enhance the mechanistic understanding of cholestasis. We analysed BA levels in various tissues of Benign Recurrent Intrahepatic Cholestasis type 2 (BRIC2) patients and our simulations suggest a higher susceptibility of BRIC2 patients toward cholestatic DILI due to BA accumulation in the liver. The effect of drugs on systemic BA levels were simulated for cyclosporine A (CsA). Our results confirmed the higher risk of DILI after CsA administration in healthy and BRIC2 patients. The presented PBBA model enhances our mechanistic understanding underlying cholestasis and drug-induced alterations of BA levels in blood and organs. The developed PBBA model might be applied in the future to anticipate potential risk of cholestasis in patients.

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

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

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