Inhibition of hepatic PCSK9 as a novel therapeutic target ameliorates metabolic steatohepatitis in mice

Background & Aims

Metabolic steatohepatitis (MASH) is closely related to metabolic disorders, and the main characteristics of MASH are hepatocyte steatosis with hepatocyte injury and inflammation. In severe cases, MASH can develop into liver cirrhosis. At present, there is no effective treatment for MASH. Proprotein convertase subtilisin/kexin 9 (PCSK9) is a popular target for the development of cholesterol-lowering drugs and therapeutic interventions for cardiovascular disease. The present study aimed to explore the role of PCSK9 in methionine- and choline-deficient (MCD) diet-induced MASH progression and its targeted intervention.

Methods

PCSK9 expression was determined in a MASH mouse model, and the role of PCSK9 in the regulation of lipid metabolism, inflammation, and fibrosis was investigated using PCSK9 knockout (PCSK9^−/−) mice fed a MCD diet. An adeno-associated virus was used to alter PCSK9 expression in MASH mice.

Results

Following the MCD diet, C57BL/6J wild-type (WT) mice developed marked steatohepatitis and elevated hepatic PCSK9 expression, and circulating PCSK9 expression. PCSK9^−/− mice showed significantly alleviated MCD-induced hepatic steatosis, with lower serum ALT levels, lower serum AST levels, smaller hepatic vacuoles, and less hepatic lipid deposition. PCSK9^−/− mice on the MCD diet showed a significantly reduced levels of inflammation and fibrogenesis. Moreover, adeno-associated virus (AAV)–mediated PCSK9 silencing in mouse livers significantly relieved liver steatosis, inflammation, and fibrosis.

Conclusions

The present study demonstrated an important role of PCSK9 in MASH, suggesting that inhibition of PCSK9 may represent a novel and effective therapeutic strategy for MASH treatment.