AI Summary
This article discusses the role of bile acids in cholestatic liver injury, focusing on how they can impact mitochondrial function, endoplasmic reticulum stress, inflammation, and autophagy. The review highlights how bile acids can induce cell death through two primary apoptotic pathways: death receptor-independent and death receptor-dependent pathways. In death receptor-independent pathways, bile acids impair the mitochondrial electron transport chain, leading to the production of reactive oxygen species and oxidative stress, ultimately resulting in cell death. In death receptor-dependent pathways, bile acids can interact with death receptors on the cell membrane to initiate apoptosis. The article delves into the mechanisms by which mitochondrial dysfunction contributes to liver injury in cholestatic conditions.
Bile acids are essential signaling molecules derived from cholesterol metabolism in the liver and are crucial for the digestion and absorption of fats. These molecules undergo further modification in the intestines by the gut microbiome. However, disruptions in bile flow, a condition known as cholestasis, can lead to the pathological accumulation of hydrophobic BAs in the liver and bloodstream. This accumulation not only exacerbates liver damage but also induces significant disturbances in cellular processes. The review focuses on recent developments in understanding how BAs contribute to liver injury by affecting mitochondrial function, endoplasmic reticulum (ER) stress, inflammation, and autophagy.
Pathways of hepatocyte apoptosis
Mitochondria are central to the regulation of apoptosis, the programmed cell death process, which plays a pivotal role in cholestatic liver injury. The review discusses two primary apoptotic pathways influenced by BAs: death receptor-independent and death receptor-dependent pathways.
In death receptor-independent pathways, BAs can directly impair the mitochondrial electron transport chain (ETC), leading to the production of reactive oxygen species (ROS) and oxidative stress. This stress causes the mitochondrial permeability transition pore (mPTP) to open, disrupting the mitochondrial membrane potential and ultimately leading to cell death. The release of cytochrome C from mitochondria into the cytosol triggers the intrinsic pathway of apoptosis, culminating in the activation of caspase enzymes that execute cell death.
In death receptor-dependent pathways, BAs can interact with death receptors on the cell membrane, such as the FAS receptor, to initiate apoptosis. This interaction leads to the formation of a death-inducing signaling complex