Obeticholic acid orchestrates the crosstalk between ileal autophagy and tight junctions in non-alcoholic steatohepatitis: Role of TLR4/TGF-β1 axis

Tawfiq, Rasha A.; Nassar, Noha N.; Hammam, Olfat; Allam, Rasha M.; Elmazar, Mohamed M.; Abdallah, Dalaal M.; Attia, Yasmeen M.

doi:10.1016/j.cbi.2022.109953

Cited by 11 publications

(7 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, further research is required to evaluate the therapeutic effects and detail the possible side effects of OCA across various indicators to enhance Given the pivotal role of fibrosis in the progression of NASH, anti-fibrosis treatment is essential. [26] OCA, through its inhibition of the transforming growth factor gene, [27] currently remains the only well-recognized approach for alleviating NASH-related fibrosis. In our meta-analysis, OCA demonstrated a significant improvement in fibrosis without worsening NASH symptoms with an OR of 2.44 (95% CI: 1.65-3.61).…”

Section: Months Pathologymentioning

confidence: 99%

The effect and safety of obeticholic acid for patients with nonalcoholic steatohepatitis: A systematic review and meta-analysis of randomized controlled trials

Zhao,

Li,

Zhang

et al. 2024

Medicine

View full text Add to dashboard Cite

Background and aims: Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) is one of the primary causes of chronic liver disease worldwide. Obeticholic acid (OCA), a potent farnesoid X nuclear receptor activator, has shown promise for treating NASH-related fibrosis due to its anti-fibrotic effects. This study aimed to examine the efficacy of OCA for patients with NASH as well as to investigate its impact on dyslipidemia. Method: A search of databases including PubMed, Embase, and Cochrane Library from January 1, 2010, to November 1, 2022, was conducted to identify systematic reviews of randomized controlled trials involving NASH patients. Inclusion criteria comprised randomized controlled trials that specifically addressed NASH as diagnosed through magnetic resonance imaging, computed tomography, or histology. The results were then categorized, with consideration given to both biochemical and histological outcomes. Result: Five NASH studies were ultimately selected for further analysis. In terms of biochemical indicators, patients receiving OCA treatment showed improvements in alanine transaminase (mean difference: −19.48, 95% confidence interval [CI]: −24.39 to 14.58; P < .05) and aspartate aminotransferase (mean difference: −9.22, 95% CI: −12.70 to 5.74; P < .05). As for histological improvement, OCA treatment reduced fibrosis (odds ratio [OR]: 1.95, 95% CI: 1.47–2.59; P = .001) and steatosis (OR: 1.95, 95% CI: 1.47–2.59; P = .001). No significant differences were observed regarding adverse events (1.44, 95% CI: 0.57–3.62; P > .001). Regarding dyslipidemia, mean differences between total cholesterol and low-density lipoprotein were found to be high (0.33, 95% CI: 0.01–0.64, P < .05; 0.39, 95% CI: 0.04–0.73, P < .05). In the case of pruritus, OCA achieved a high OR (3.22, 95% CI: 2.22–4.74) compared with placebo. Conclusion: OCA also reduced several liver test markers compared to placebo, including the biochemical indicators alanine transaminase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase, and improved hepatocellular ballooning, fibrosis, steatosis, and lobular inflammation. Although the incidence of adverse events did not significantly differ between OCA and placebo groups among NASH patients, OCA treatment was found to elevate total cholesterol and low-density lipoprotein levels, and the reported severity of pruritus increased with higher doses of OCA.

show abstract

Section: Months Pathologymentioning

confidence: 99%

The effect and safety of obeticholic acid for patients with nonalcoholic steatohepatitis: A systematic review and meta-analysis of randomized controlled trials

Zhao,

Li,

Zhang

et al. 2024

Medicine

View full text Add to dashboard Cite

show abstract

“…OCA, a CDCA derivative and FXR agonist, interfered with TLR4/TGF-β1 signaling to activate autophagy and intestinal integrity in NASH [61][62][63]. TUDCA attenuated the progression of HFD-induced NAFLD in mice and was associated with less gut inflammation, better intestinal barrier function, and changes in the microbiota composition [64].…”

Section: Non-alcoholic Fatty Liver Disease (Nafld)mentioning

confidence: 99%

Bile Acids, Intestinal Barrier Dysfunction, and Related Diseases

Shi

Jin

Huang

2023

Cells

View full text Add to dashboard Cite

The intestinal barrier is a precisely regulated semi-permeable physiological structure that absorbs nutrients and protects the internal environment from infiltration of pathological molecules and microorganisms. Bile acids are small molecules synthesized from cholesterol in the liver, secreted into the duodenum, and transformed to secondary or tertiary bile acids by the gut microbiota. Bile acids interact with bile acid receptors (BARs) or gut microbiota, which plays a key role in maintaining the homeostasis of the intestinal barrier. In this review, we summarize and discuss the recent studies on bile acid disorder associated with intestinal barrier dysfunction and related diseases. We focus on the roles of bile acids, BARs, and gut microbiota in triggering intestinal barrier dysfunction. Insights for the future prevention and treatment of intestinal barrier dysfunction and related diseases are provided.

show abstract

“…The activation of intestinal FXR also directly affects intestine inflammatory responses by inhibiting the activation of the Toll-like receptor (TLR) signaling pathway in the intestinal epithelium to reduce the production of cytokines and the severity of the inflammatory response . Additionally, FXR can regulate autophagy and apoptosis in intestinal epithelial cells to protect the integrity and functions of cells. , Clinically, a poor expression level of FXR has been observed in patients with enterocolitis, and the activation of FXR can significantly alleviate the symptoms and inflammatory response in patients, and meanwhile improve the architecture and function of the gut microbiome . These findings indicated that FXR is a promising therapeutic target for IBD, and developing intestinal-targeted FXR agonists may be an effective strategy to conquer this complicated intestinal disease.…”

Section: Introductionmentioning

confidence: 99%

Discovery and Optimization of Novel Nonbile Acid FXR Agonists as Preclinical Candidates for the Treatment of Inflammatory Bowel Disease

Li,

Xu,

Zhao

et al. 2024

J. Med. Chem.

View full text Add to dashboard Cite

Inflammatory bowel disease (IBD) is a multifactorial chronic inflammation of the intestine and has become a global public health concern. A farnesoid X receptor (FXR) was recently reported to play a key role in hepatic-intestinal circulation, intestinal metabolism, immunity, and microbial regulation, and thus, it becomes a promising therapeutic target for IBD. In this study, we identified a series of nonbile acid FXR agonists, in which 33 novel compounds were designed and synthesized by the structure-based drug design strategy from our previously identified hit compound. Compound 33 exhibited a potent FXR agonistic activity, high intestinal distribution, good anti-inflammatory activity, and the ability to repair the colon epithelium in a DSS-induced acute enteritis model. Based on the results of RNA-seq analysis, we further investigated the therapeutic potential of the combination of compound 33 with 5-ASA. Overall, the results indicated that compound 33 is a promising drug candidate for IBD treatment.

show abstract

Obeticholic acid orchestrates the crosstalk between ileal autophagy and tight junctions in non-alcoholic steatohepatitis: Role of TLR4/TGF-β1 axis

Cited by 11 publications

References 44 publications

The effect and safety of obeticholic acid for patients with nonalcoholic steatohepatitis: A systematic review and meta-analysis of randomized controlled trials

The effect and safety of obeticholic acid for patients with nonalcoholic steatohepatitis: A systematic review and meta-analysis of randomized controlled trials

Bile Acids, Intestinal Barrier Dysfunction, and Related Diseases

Discovery and Optimization of Novel Nonbile Acid FXR Agonists as Preclinical Candidates for the Treatment of Inflammatory Bowel Disease

Contact Info

Product

Resources

About