The molecular pathogenesis of cholestasis in sepsis

Abstract

Sepsis-induced cholestasis is a complication of infection. Infections cause systemic and intrahepatic increase in proinflammatory cytokines which result in impaired bile flow ie. cholestasis. Several other mediators of impairment in bile flow have been identified under conditions of sepsis such as increased nitric oxide production and decreased aquaporin channels. The development of cholestasis may also further worsen inflammation. The molecular basis of normal bile flow and mechanisms of impairment in sepsis are discussed.

Advances in sepsis-associated liver dysfunction

“…[24] LPS induces KCs to release pro-inflammatory cytokines which lead to downregulation of transporters involved in bile flow, coordinated by nuclear receptors and transcription factors. [25] The transporters that are downregulated include MRP2, organic aniontransporting polypeptides (OATPs), bile salt export pump (BSEP), multiple drug resistance (MDR)-1 transporter, Na + , K + -ATPase and sodium-dependent taurocholate cotransporting polypeptide (NTCP). Reduced basolateral bile acid uptake appears to be related to a reduction in the expression of NTCP and OATPs.…”

Phytosterols Promote Liver Injury and Kupffer Cell Activation in Parenteral Nutrition–Associated Liver Disease

“…In this in vitro model focusing on phytosterol-mediated alterations in nuclear receptor–mediated gene expression, stigmasterol antagonized FXR signaling, but the most prevalent phytosterol in soy lipid, β-sitosterol, did not (14). Proinflammatory cytokine-induced cell signaling in hepatocytes, primarily derived from LPS-activated Kupffer cells residing in hepatic sinusoids, also suppresses nuclear receptor–mediated gene expression in liver, including FXR-dependent pathways (referred to as cytokine-mediated cholestasis) (20–22). Thus, the combination of cytokine signaling and plant sterols could potentially exert synergistic potent inhibitory effects on hepatocyte expression of canalicular transport systems and thus promote intracellular bile salt retention or cholestasis.…”

Untitled

“…It is pointed out that BDL induces kind of liver fibrosis that pathogenically and physiologically 29 . The degeneration and death of hepatocellular showed in cholestasis that related to the accumulation of toxic bile salt, which stimulation of oxidative stress through the opening of nicotinamide adenine dinucleotide phosphate oxidase isoform into the pathway of immune activation 30 . It has been implicated that hepatocyte necrosis and apoptosis involved with stimulation of kuffar cells which release tumor necrosis factor and TGF-β 8 .…”