Deciphering the Intestinal Intracellular role of PCSK9 – Int2PCSK9
Hypercholesterolemia is a major risk factor for cardiovascular diseases (CVD). Current guidelines highlight the need for new treatment options able to decrease plasma cholesterol levels beyond those presently achieved. Discovered in 2003, the Proprotein Convertase Subtilisin Kexin of Type 9 (PCSK9) is a natural inhibitor of the LDL receptor and plays a critical role in cholesterol homeostasis. The existence of patients harboring PCSK9 mutations who are highly protected against CVD has initiated the search for safe anti-PCSK9 drugs. Promising anti-PCSK9 therapies have been recently approved by the FDA but there is still much to be understood about PCSK9 biology notably its extra-hepatic functions.
The generation of liver-specific PCSK9 knockout mice clearly demonstrated that PCSK9 affects significantly cholesterol homeostasis via its action on extra-hepatic organs. Beside the liver, the small intestine is the second organ to highly express PCSK9. We have previously that PCSK9 deficiency significantly affects postprandial lipemia and transintestinal cholesterol excretion in mice. Furthermore, we obtained recent results showing that human intestinal Caco2 cells progressively lose their ability to secrete PCSK9 during cell differentiation.
Cedric Le May (Institut du Thorax, INSERM UMR 1087 / CNRS UMR 6291, Nantes) will coordinate this 36 months project whose main objectives are 1) to determine the functional importance of intracellular intestinal PCSK9 on postprandial lipemia, cholesterol absorption and transintestinal cholesterol excretion by generating mice lacking PCSK9 in the small intestine; 2) to discover via proteomic approach factors responsible for the secretion of PCSK9.
Our project will give new insights in PCSK9 biology by unravelling the potential autonomous role of intestinal PCSK9 and by identifying new partners important for PCSK9 secretion.
Monsieur Cédric LE MAY (L’institut du thorax)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
UMR 1087 / CNRS UMR 6291 L’institut du thorax
Help of the ANR 280,905 euros
Beginning and duration of the scientific project: December 2016 - 36 Months