Bile Acid Toxicity and Protein Kinases
1Department of General Surgery, Faculty of Medicine, Gazi University, Ankara, Turkey. dr.aengin@gmail.com.
Advances in Experimental Medicine and Biology
|February 4, 2021
Summary
Hydrophobic bile acids cause liver cell death through apoptosis and inflammation. Hydrophilic bile acids, however, protect liver cells by activating protective signaling pathways. This study explores these mechanisms.
Area of Science:
- Hepatology and Molecular Biology
- Cellular signaling pathways
- Bile acid metabolism and toxicity
Background:
- Bile acids, essential for digestion, can cause hepatocyte injury at pathological concentrations during cholestasis.
- Hydrophobic bile acids induce apoptosis, while hydrophilic bile acids activate protective signaling cascades like cAMP, MAPK, and PI3K pathways.
- Cell death mechanisms, including apoptosis and necroptosis, are intricately regulated by protein kinase signaling.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying bile acid-induced hepatocyte apoptosis, inflammation, and necroptosis.
- To investigate the role of protein kinase signaling in mediating the effects of hydrophobic and hydrophilic bile acids.
- To understand how bile acids modulate death receptor pathways and mitochondrial apoptotic pathways.
Main Methods:
- Analysis of apoptotic pathways controlled by protein kinase signaling.
- Investigation of death receptor-mediated apoptosis regulation at the cell surface and DISC.
- Examination of mitochondrial apoptotic pathways involving Bcl-2 family proteins.
- Exploration of ROS signaling in Fas receptor activation and necroptosis signaling.
Main Results:
- Hydrophobic bile acids upregulate inflammatory responses and promote apoptosis by preventing cFLIP recruitment to the DISC.
- Mitochondrial apoptosis is regulated by Bcl-2 family proteins controlling cytochrome c release.
- Fas receptor activation involves NADPH oxidase-dependent ROS signaling, while necroptosis activation requires RIP1 kinase activity.
Conclusions:
- Protein kinase signal transduction plays a critical role in mediating hydrophobic bile acid-induced inflammation, apoptosis, necroptosis, and necrosis.
- Understanding these pathways is crucial for developing therapeutic strategies against cholestatic liver injury.
- Differential effects of hydrophobic and hydrophilic bile acids highlight complex cellular responses to bile acid homeostasis disruption.
Keywords:
Apical sodium bile acid cotransporter (ASBT)Bile acidCanalicular bile salt export pump (BSEP)CholangiocytesGlycochenodeoxycholic acid (GCDCA)Hydrophobic bile acidsNa+/taurocholate (TC) cotransporter (NTCP)Tauroursodeoxycholic acid (TUDCA)Transmembrane G-protein-coupled receptor (TGR5)Ursodeoxycholic acid (UDCA)
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