Proprotein convertase subtilisin kexin type 9 (PCSK9) is a natural inhibitor of the low density lipoprotein receptor (LDLr) and its deficiency confers a high protection against cardiovascular diseases. We previously reported that PCSK9 expression is regulated by nutritional status and insulinemia.

Here, we investigated the metabolic adaptation of PCSK9 deficient mice (PCSK9-/-) in response to a high fat diet (HFD).

PCSK9-/- and PCSK9+/+ males were given a 60 % fat diet for 10 weeks. Before treatment, both genotypes responded similarly to oral glucose tolerance (OGTT) and insulin tolerance test (ITT). The first week following HFD feeding, we noticed an initial rise in glycemia for both genotypes (32 and 37.8 %), reflecting diet-induced insulin resistance. Despite comparable OGTT and ITT, PCSK9-/- mice presented a slight reduction of blood glucose compared to PCSK9+/+ littermates during the all period of HFD feeding. By contrast, PCSK9 deficiency did not alter body weight, plasma triglyceride or free fatty acids levels in response to HFD. On regular diet, PCSK9-/- mice have significant reduction of circulating cholesterol compared to PCSK9+/+ mice (0.721±0.05 g/l vs 1.06±0.04 P=0.0002). Surprisingly, after one week of diet, this phenotype was lost and cholesterol levels were not significantly different between PCSK9-/- and PCSK9+/+ mice (respectively: 1.327±0.07 g/l vs 1.501±0.05 P=0.065).

Here, we demonstrated that under HFD, PCSK9 deficiency did not affect weight gain, insulin sensitivity or plasma triglyceride levels. However, the absence of PCSK9 didn’t prevent hypercholesterolemia, suggesting a cross talk between PCSK9- mediated LDLr degradation and the molecular pathways affected by a dietary fat excess.