LIPID METABOLISM: Edited by Kausik K. Ray and G. Kees HovinghRole of PCSK9 beyond liver involvementCariou, Bertranda,b,c; Si-Tayeb, Karima; Le May, CédricaAuthor Information aInserm, UMR1087-CNRS UMR6291, l’Institut du Thorax bUniversité de Nantes, Faculté de Médecine, Institut du Thorax cDepartment of Endocrinology, l’Institut du Thorax, University Hospital of Nantes, Nantes, France Correspondence to Bertrand Cariou, Clinique d’Endocrinologie, l’Institut du Thorax, Hôpital Guillaume & René Laennec, Boulevard Jacques Monod, 44093 Nantes cedex, France. Tel: +33 2 53 48 27 07; fax: +33 2 53 48 27 08; e-mail: firstname.lastname@example.org. Current Opinion in Lipidology: June 2015 - Volume 26 - Issue 3 - p 155-161 doi: 10.1097/MOL.0000000000000180 Buy Metrics Abstract Purpose of review Proprotein convertase subtilisin kexin type 9 (PCSK9) acts as an endogenous natural inhibitor of the LDL receptor pathway, by targeting the receptor to lysosomes for degradation. Beside the liver, PCSK9 is also expressed at significant levels in other tissues, where its function remains unclear. The current review focuses on the extrahepatic actions of PCSK9. Recent findings The generation of liver-specific PCSK9 knockout mice has clearly indicated that PCSK9 affects cholesterol homeostasis via its action on extrahepatic organs. PCSK9 is highly expressed in the intestine, where it controls the production of triglyceride-rich lipoproteins and the transintestinal cholesterol excretion. The role of PCSK9 in the endocrine pancreas and glucose homeostasis remains unclear because conflicting data exist concerning the metabolic phenotype of PCSK9-deficient mice. Sparse data suggest that PCSK9 might also play a role in kidneys, vascular smooth muscle cells, and neurons. Summary Based on the virtuous combination of genetic and pharmacological approaches, the major function of PCSK9 as a key regulator of hepatic LDL receptor metabolism had quickly emerged. Accumulating evidence indicates that intestinal PCSK9 is also involved in the modulation of lipid homeostasis. Additional studies are warranted to decipher the physiological function of PCSK9 in other extrahepatic tissues and thus to better assess the safety of PCSK9 inhibitors. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.