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. Author manuscript; available in PMC: 2020 Jul 15.
Published in final edited form as: Chem Res Toxicol. 2019 Jun 18;32(7):1327–1334. doi: 10.1021/acs.chemrestox.9b00148

Figure 1.

Figure 1

Cholestatic liver injury can be initiated by 3 types of triggering factors, namely (i) transporter changes, such as transport inhibition, reduced expression and/or aberrant subcellular localization of bile transporters, (ii) hepatocellular changes, including compromised cytoskeletal architecture, disruption of tight junctions and decreased membrane fluidity, and (iii) altered bile canaliculi dynamics, namely dilatation or constriction of bile canaliculi. These stimuli induce bile accumulation, which subsequently activates 2 cellular responses, a deteriorative response and an adaptive response. The deteriorative response is typified by the occurrence of mitochondrial impairment, different cell death modes, endoplasmic reticulum (ER) stress with unfolded protein responses (UPR), oxidative stress and inflammation. The adaptive response strives to counteract bile acid accumulation via activation of a number of nuclear receptors.