The role of PCSK9 in NAFLD/NASH and therapeutic implications of PCSK9 inhibition

Introduction There are inconsistent findings regarding the effect of lipid-lowering agents on nonalcoholic fatty liver disease (NAFLD). Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is an important player in cholesterol homeostasis and intracellular lipogenesis, and PCSK9 inhibitors (PCSK9-i) have been found to be efficient for pharmacological management of hyperlipidemia. Areas covered Whether PCSK9 (itself) or PCSK9-i affects NAFLD is still disputed. To address this question, we review published preclinical and clinical studies providing evidence for the role of PCSK9 in and the effect of PCSK9-I on the development and pathogenesis of NAFLD. Expert opinion The current evidence from a landscape of preclinical and clinical studies examining the role of PCSK9 in NAFLD shows controversial results. Preclinical studies indicate that PCSK9 associates with NAFLD and nonalcoholic steatohepatitis (NASH) progression in opposite directions. In humans, it has been concluded that the severity of hepatic steatosis affects the correlation between circulating PCSK9 and liver fat content in humans, with a possible impact of circulating PCSK9 in the early stages of NAFLD, but not in the late stages. However, data from clinical trials with PCSK9-i reassure to the safety of these agents, although real-life long-term evidence is needed.