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

ABSTRACT

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.

KEYWORDS:

• Nonalcoholic fatty liver
• nonalcoholic steatohepatitis
• PCSK9

Article highlights

• PCSK9 deficient mice under NAFL-inducing challenge show resistance to hepatic steatosis under NAFLD-inducing challenge.

• PCSK9 deficient mice under NASH-induced challenge show exacerbated steatohepatitis and liver fibrosis.

• There is a normal liver function or protection against NAFLD in humans carrying PCSK9 LOF mutations.

• The correlation between circulating PCSK9 levels and liver fat content in humans depends on the severity and stage of hepatic steatosis.

• PCSK9 inhibitors exert ameliorating effects on hepatic steatosis, inflammation, and fibrosis.

Declaration of interest

M Banach has disclosed receiving speakers bureau from Amgen, Herbapol, Kogen, KRKA, Polpharma, Mylan/Viatris, Novartis, Novo-Nordisk, Sanofi-Aventis, Teva, and Zentiva; being a consultant to Abbott Vascular, Amgen, Daichii Sankyo, Esperion, FreiaPharmaceuticals, Novartis, Polfarmex, Sanofi-Aventis; Grants from Amgen, Mylan/Viatris, Sanofi and Valeant. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Acknowledgement

The research activity of MR was partially funded by Banca di Credito Cooperativo di Milano.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.