Publications

Inflammation induces marked changes in lipid and lipoprotein metabolism. Proprotein convertase subtilisin kexin 9 (PCSK9) plays an important role in regulating LDL receptor degradation. Here, we demonstrate that LPS decreases hepatic LDL receptor protein but at the same time hepatic LDL receptor mRNA levels are not decreased. We therefore explored the effect of LPS on PCSK9 expression. LPS results in a marked increase in hepatic PCSK9 mRNA levels (4h 2.5-fold increase; 38h 12.5-fold increase). The increase in PCSK9 is a sensitive response with 1microg LPS inducing a (1/2) maximal response. LPS also increased PCSK9 expression in the kidney. Finally, zymosan and turpentine, other treatments that induce inflammation, also stimulated hepatic expression of PCSK9. Thus, inflammation stimulates PCSK9 expression leading to increased LDL receptor degradation and decreasing LDL receptors thereby increasing serum LDL, which could have beneficial effects on host defense.

OBJECTIVE

To determine if neighborhood socioeconomic status (SES) is independently related to physical and mental health outcomes in systemic lupus erythematosus (SLE).

METHODS

Data derived from the first 3 waves of the Lupus Outcomes Study, a telephone survey of 957 patients with confirmed SLE diagnoses, recruited from clinical and non-clinical sources. Residential addresses were geocoded to U.S. Census block groups. Outcome measures included the Systemic Lupus Activity Questionnaire (SLAQ) score, a self-reported assessment of SLE symptoms; the Medical Outcomes Study Short Form-36 Health Survey physical functioning score; and Center for Epidemiologic Studies-Depression (CES-D) score of > or = 19 points. Multivariate analyses adjusted for race/ethnicity and other demographic and health-related covariates.

RESULTS

After adjustment, lower individual SES, measured by education, household income, or poverty status, was associated with all outcomes. In models that did not include individual SES, low neighborhood SES (> 30% of residents in poverty) was also associated with poor outcomes. After adjustment for individual SES, demographic, and health-related covariates, only CES-D > or = 19 remained associated with neighborhood SES: 47% [95% confidence interval (CI) 38-56%] versus 35% (95% CI 32-37%).

CONCLUSION

Individual SES is associated with physical and mental health outcomes in persons with SLE. Low neighborhood SES contributes independently to high levels of depressive symptoms. Future research should focus on mechanisms underlying these differences.

In an effort to discover new mouse models of cardiovascular disease using N-ethyl-N-nitrosourea (ENU) mutagenesis followed by high-throughput phenotyping, we have identified a new mouse mutation, C699Y, in the LDL receptor (Ldlr), named wicked high cholesterol (WHC). When WHC was compared with the widely used Ldlr knockout (KO) mouse, notable phenotypic differences between strains were observed, such as accelerated atherosclerotic lesion formation and reduced hepatosteatosis in the ENU mutant after a short exposure to an atherogenic diet. This loss-of-function mouse model carries a single base mutation in the Ldlr gene on an otherwise pure C57BL/6J (B6) genetic background, making it a useful new tool for understanding the pathophysiology of atherosclerosis and for evaluating additional genetic modifiers regulating hyperlipidemia and atherogenesis. Further investigation of genomic differences between the ENU mutant and KO strains may reveal previously unappreciated sequence functionality.