APOA4-PCSK9 interaction during lithogenesis and effects on cholesterol metabolism and lithogenesis. (IMAGE)
Caption
Gut microbiota produce trimethylamine, which enters the liver via the portal circulation and is primarily oxidized by FMO3 to produce TMAO. TMAO upregulates hepatic PCSK9 gene expression while downregulating APOA4 expression. PCSK9 overexpression inhibits APOA4 expression, while low APOA4 expression further promotes PCSK9 expression, forming a feedback loop that dysregulates cholesterol metabolism. This upregulates cholesterol synthesis by HMGCR and cholesterol efflux by ABCG5/8. Consequently, biliary concentrations of cholesterol and bile acids increase and decrease, respectively, thereby promoting cholesterol gallstone formation. TMAO, trimethylamine-N-oxide; APOA4, apolipoprotein A4; PCSK9, proprotein convertase subtilisin/kexin type 9; ABCG5, ATP-binding cassette sub-family G member 5; ABCG8, ATP-binding cassette sub-family G member 8; FMO3, flavin containing monooxygenase 3; TMA, Trimethylamine.
Credit
Xianzhi Meng, Chao Shi, Jingjing Yu, Ziang Meng
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License
CC BY-NC