👤 Carissa Thornock

Patients with chronic kidney disease (CKD) are at high risk for CVD. However, traditional lipid risk factors, including low HDL levels, cannot completely explain the increased risk. Altered HDL proteome is linked with both CVD and CKD, but the role of HDL proteins in incident CVD events in patients with CKD is unknown. In this prospective case-control study, we used targeted proteomics to quantify 31 HDL proteins in 92 subjects (46 incident new CVD and 46 one-to-one matched controls) at various stages of CKD. We tested associations of HDL proteins with incident CVD using matched logistic regression analysis. In the model fully adjusted for clinical confounders, lipid levels, C-reactive protein, and proteinuria, no significant associations were found for HDL-C, but we observed inverse associations between levels of HDL proteins paraoxonase/arylesterase 1 (PON1), paraoxonase/arylesterase 3 (PON3), and LCAT and incident CVD. Odds ratios (per 1 SD) were 0.38 (0.18-0.97, P = 0.042), 0.42 (0.20-0.92, P = 0.031), and 0.30 (0.11-0.83, P = 0.020) for PON1, PON3, and LCAT, respectively. Apolipoprotein A-IV remained associated with incident CVD in CKD patients in models adjusted for clinical confounders and lipid levels but lost significance with the addition of C-reactive protein and proteinuria to the model. In conclusion, levels of four HDL proteins, PON1, PON3, LCAT, and apolipoprotein A-IV, were found to be inversely associated with incident CVD events in CKD patients. Our observations indicate that HDLs' protein cargo, but not HDL-C levels, can serve as a marker-and perhaps mediator-for elevated CVD risk in CKD patients. Show less

Loss-of-function mutations in the transcription factor CREB3L3 (CREBH) associate with severe hypertriglyceridemia in humans. CREBH is believed to lower plasma triglycerides by augmenting the activity of lipoprotein lipase (LPL). However, by using a mouse model of type 1 diabetes mellitus (T1DM), we found that greater liver expression of active CREBH normalized both elevated plasma triglycerides and cholesterol. Residual triglyceride-rich lipoprotein (TRL) remnants were enriched in apolipoprotein E (APOE) and impoverished in APOC3, an apolipoprotein composition indicative of increased hepatic clearance. The underlying mechanism was independent of LPL, as CREBH reduced both triglycerides and cholesterol in LPL-deficient mice. Instead, APOE was critical for CREBH's ability to lower circulating remnant lipoproteins because it failed to reduce TRL cholesterol in Apoe-/- mice. Importantly, individuals with CREB3L3 loss-of-function mutations exhibited increased levels of remnant lipoproteins that were deprived of APOE. Recent evidence suggests that impaired clearance of TRL remnants promotes cardiovascular disease in patients with T1DM. Consistently, we found that hepatic expression of CREBH prevented the progression of diabetes-accelerated atherosclerosis. Our results support the proposal that CREBH acts through an APOE-dependent pathway to increase hepatic clearance of remnant lipoproteins. They also implicate elevated levels of remnants in the pathogenesis of atherosclerosis in T1DM. Show less