Liver fat accumulation is associated with circulating PCSK9 levels

Introduction: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver damage and associates with cardiovascular disease independently of classic risk factors. The pathogenesis of accelerated atherogenesis is under definition, but NAFLD is characterized by altered lipoprotein metabolism. Furthermore, the progressive form of liver disease, namely steatohepatitis (NASH), is associated with hepatic cholesterol accumulation. Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is an important player in lipoprotein metabolism. Cleaved PCSK9 is secreted by hepatocytes and inhibits the uptake of low-density lipoproteins by targeting the receptor for degradation. PCSK9 loss-of-function mutations and anti-PCKS9 drugs reduce circulating cholesterol and protect from cardiovascular disease. Aim: To evaluate whether histological hepatic fat content and liver damage affect circulating PCSK9 levels. Material and methods: We considered 201 consecutive Italian patients, who underwent liver biopsy for suspected NASH (n = 126 for persistently elevated ALT, n = 77 for severe obesity). Liver damage was quantified according to the NAFLD activity score. Serum PCSK9 levels were measured by ELISA (R&D Systems, Minneapolis, MN, USA). Hepatic PCSK9 mRNA levels were analyzed by qRT-PCR in a subset of obese subjects (n = 30). Results: Circulating PCSK9 levels were associated with both steatosis grade (estimate +0.18 ± 0.06 log ng/mL; p = 0.0011), and steatosis related liver damage: necro-inflammation (+0.27 ± 0.07; p < 0.001), hepatocellular ballooning (+0.28 ± 0.99 log ng/mL; p = 0.005), and fibrosis stage (+0.16 ± 0.05; p = 0.001). At multivariate analysis, PCSK9 levels were associated with steatosis grade (+0.13 ± 0.06 log ng/mL; p = 0.03), age (estimate +0.009 ± 0.004; p = 0.03), and BMI (estimate -0.016 ± 0.006; p = 0.01), independently of sex and of liver fibrosis stage. There was no significant association between circulating PCSK9 concentration and hepatic mRNA levels. Conclusions: Circulating PCSK9 levels increase with the severity of hepatic fat accumulation in patients at risk of NASH. Modulation of PCSK9 release by post-transcriptional mechanisms might be involved in mediating atherosclerosis progression in NAFLD patients, with potential therapeutic implications.