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PCSK7: Linking atherogenic dyslipidaemia and inflammation in non-alcoholic fatty liver disease?

Genetic studies played an integral role in elucidation of the role of PCSK9 (proprotein convertase subtilisin/kexin type 9) in cholesterol homeostasis and as a potential therapeutic target, subsequently validated by cardiovascular outcomes studies. Now, genetic insights link PCSK7, another member of the subtilisin-like proprotein convertase family, with dyslipidaemia and severity of liver disease in high-risk individuals. In the latest study, the effects of genetic variation in PCSK7 expression on non-alcoholic fatty liver disease-related traits were evaluated in 1,801 individuals from the Liver Biopsy Cohort, 500,000 individuals from the UK Biobank Cohort, and 4,580 from the Dallas Heart Study. The PCSK7 rs236918 C variant was associated with higher triglycerides and aminotransferase levels, and more severe hepatic inflammation in the Liver Biopsy Cohort (p < 0.05), as well as hypercholesterolaemia and liver disease in the UK Biobank Cohort. PCSK7 missense variants were also associated with circulating lipids in the Dallas Heart Study cohort. In vitro studies showed that the PCSK97 rs236918 C variant upregulates a new "intra-PCSK7" long noncoding RNA, which correlates with plasma triglycerides in vivo (p = 0.04). These findings suggest that the potential of PCSK7 targeting in non-alcoholic fatty liver disease may merit investigation.
PCSK7 gene variation bridges atherogenic dyslipidemia with hepatic inflammation in NAFLD patients.

Dongiovanni P, Meroni M, Baselli G et al.