<i>PCSK9</i> rs11591147 R46L Loss-of-Function Variant Protects Against Liver Damage in Individuals with NAFLD

The role of hepatic lipid composition in obesity‐related metabolic disease

“…140,141 Conversely, no effects of n-3 PUFA supplementation on histological features of NASH were reported however. 140,141 Interestingly, n-3 PUFA supplementation in a diet-induced murine Most, [144][145][146] but not all, 147 studies demonstrate positive associations between circulating concentrations and hepatic expression of PSCK9 and steatosis severity, whilst it was recently found that the PCSK9 R46L loss-of-function genetic variant was protective from hepatic steatosis and the histological features of NASH. 146 Experimentally, preliminary evidence has shown that two different PCSK9 inhibitors were successful in ameliorating hepatic steatosis and resolving NASH in 40 patients with heterozygous familial hyperlipidaemia.…”

“…140,141 Interestingly, n-3 PUFA supplementation in a diet-induced murine Most, [144][145][146] but not all, 147 studies demonstrate positive associations between circulating concentrations and hepatic expression of PSCK9 and steatosis severity, whilst it was recently found that the PCSK9 R46L loss-of-function genetic variant was protective from hepatic steatosis and the histological features of NASH. 146 Experimentally, preliminary evidence has shown that two different PCSK9 inhibitors were successful in ameliorating hepatic steatosis and resolving NASH in 40 patients with heterozygous familial hyperlipidaemia. 148 No studies have examined the relationship between PCSK9 inhibition and hepatic lipid composition, although multiple studies report positive associations between PCSK9 and hepatic expression of DNL-related genes.…”

“…148 No studies have examined the relationship between PCSK9 inhibition and hepatic lipid composition, although multiple studies report positive associations between PCSK9 and hepatic expression of DNL-related genes. [144][145][146] Therefore, PCSK9 inhibition may theoretically promote a less saturated hepatic lipid profile through a reduction in DNL; however, this hypothesis needs to be tested experimentally.…”

“…Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are an emerging pharmacotherapy which reduce circulating low‐density lipoproteins and cardiovascular risk by inhibiting the PCSK9‐mediated lysosomal degradation of the low‐density lipoprotein receptor 120 . Most, 144‐146 but not all, 147 studies demonstrate positive associations between circulating concentrations and hepatic expression of PSCK9 and steatosis severity, whilst it was recently found that the PCSK9 R46L loss‐of‐function genetic variant was protective from hepatic steatosis and the histological features of NASH 146 . Experimentally, preliminary evidence has shown that two different PCSK9 inhibitors were successful in ameliorating hepatic steatosis and resolving NASH in 40 patients with heterozygous familial hyperlipidaemia 148 .…”

“…Experimentally, preliminary evidence has shown that two different PCSK9 inhibitors were successful in ameliorating hepatic steatosis and resolving NASH in 40 patients with heterozygous familial hyperlipidaemia 148 . No studies have examined the relationship between PCSK9 inhibition and hepatic lipid composition, although multiple studies report positive associations between PCSK9 and hepatic expression of DNL‐related genes 144‐146 . Therefore, PCSK9 inhibition may theoretically promote a less saturated hepatic lipid profile through a reduction in DNL; however, this hypothesis needs to be tested experimentally.…”