The Effect of PCSK9 Loss-of-Function Variants on the Postprandial Lipid and ApoB-Lipoprotein Response.

Context: Proprotein convertase subtilisin kexin 9 (PCSK9) mediates degradation of the low-density lipoprotein receptor (LDLR), thereby increasing plasma low-density lipoprotein cholesterol (LDL-C). Variations in the PCSK9 gene associated with loss of function (LOF) of PCSK9 result in greater expression of hepatic LDLR, lower concentrations of LDL-C, and protection from cardiovascular disease (CVD). Apolipoprotein-B (apoB) remnants also contribute to CVD risk and are similarly cleared by the LDLR. We hypothesized that PCSK9-LOF carriers would have lower fasting and postprandial remnant lipoproteins on top of lower LDL-C. Objective: To compare fasting and postprandial concentrations of triglycerides (TGs), total apoB, and apoB48 as indicators of remnant lipoprotein metabolism in PCSK9-LOF carriers with those with no PCSK9 variants. Design: Case-control, metabolic study. Setting: Clinical Research Center of The Ottawa Hospital. Participants: Persons with one or more copies of the L10ins/A53V and/or I474V and/or R46L PCSK9 variant and persons with no PCSK9 variants. Intervention: Oral fat tolerance test. Main Outcomes Measures: Fasting and postprandial plasma TG, apoB48, total apoB, total cholesterol, and PCSK9 were measured at 0, 2, 4, and 6 hours after an oral fat load. Results: Participants with PCSK9-LOF variants (n = 22) had reduced fasting LDL-C (-14%) as well as lower fasting TG (-21%) compared with noncarrier controls (n = 23). LOF variants also had reduced postprandial total apoB (-17%), apoB48 (-23%), and TG (-18%). Postprandial PCSK9 declined in both groups (-24% vs -16%, respectively). Conclusions: Participants carrying PCSK9-LOF variants had attenuated levels of fasting and postprandial TG, apoB48, and total apoB. This may confer protection from CVD and further validate the use of PCSK9 inhibitors to lower CVD risk.

Paradoxically decreased HDL-cholesterol levels associated with rosiglitazone therapy.

OBJECTIVE: To report 2 cases of very low high-density lipoprotein cholesterol (HDL-C) levels associated with rosiglitazone therapy. CASE SUMMARY: Two patients with type 2 diabetes taking rosiglitazone for glycemic control developed paradoxically low HDL-C levels during rosiglitazone therapy. In the first patient, the HDL-C level decreased from 33 to 11.6 mg/dL after 8 months of therapy. The second patient's HDL-C level decreased from the baseline level of 44.8 mg/dL to 19.7 mg/dL after 4 months of rosiglitazone use. These abnormalities resolved on discontinuation of rosiglitazone and were not observed when the patients were treated with pioglitazone. The patients had no changes to other drug therapy or medical conditions known to affect lipid metabolism during treatment with rosiglitazone. DISCUSSION: Thiazolidinediones, insulin sensitizers widely used in the treatment of type 2 diabetes, have been reported to have beneficial effects on lipids, such as triglyceride lowering and HDL-C elevation, in addition to their glucose-lowering effects. It has been suggested that rosiglitazone and pioglitazone, the 2 currently available thiazolidinediones, may differ in their effects on lipids. As of July 2006, a total of 8 cases of paradoxical lowering of plasma HDL-C associated with rosiglitazone have now been reported. Based on use of the Naranjo probability scale, the 2 cases presented here were probably associated with rosiglitazone. The duration of therapy may be important in this paradoxical effect. CONCLUSIONS: Rosiglitazone is associated with a paradoxical decrease in HDL-C levels in patients with type 2 diabetes. In patients receiving rosiglitazone, a baseline lipid panel should be performed and lipid values should be monitored during the course of therapy.

The anti-adipogenic effect of peripheral blood mononuclear cells is absent with PCSK9 loss-of-function variants.

OBJECTIVE: To determine the effect of (1) an oral fat load and (2) pro-protein convertase subtilisin/kexin type (PCSK) 9 loss-of-function (LOF) variant status on the ability of peripheral blood mononuclear cells (PBMC) to inhibit human adipogenesis. METHODS: PBMC from subjects with one or more PCSK9 LOF variants versus non-variant controls were compared in the fasting state and after an oral fat load. RESULTS: Fasting triglyceride (TG) levels were lower in the LOF variant versus non-variant group but rose to the same level after the oral fat load. Conditioned medium from PBMC was obtained in fasting (PBMC-CM-F) and 4-h postprandial (PBMC-CM-PP) states. PBMC-CM-PP from non-variant controls inhibited adipogenesis of human preadipocytes more than did PBMC-CM-F. In contrast, PBMC-CM-F or -PP from PCSK9 LOF variant subjects had no effect on adipogenesis. After the oral fat load, PBMC from PCSK9 LOF variant subjects showed significant increases in mRNA levels of interleukin-1ß, tumor necrosis factor-α, sterol regulatory element binding protein-1c, CD36, and monocyte chemoattractant protein-1 (MCP-1), only MCP-1 mRNA levels increased in PBMC from non-variant controls. CONCLUSIONS: The absence of anti-adipogenic action of PBMC from PCSK9 LOF variant subjects points to a novel role for PCSK9 in PBMC-adipose cell interactions.