Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Molecular Mechanisms of Lupus Dyslipidemia in Mice.
Mishra1, Nilamadhab, Yan3, Kailin, Cao2, Qiang
Lupus dyslipidemia is characterized by increased total cholesterol, triglycerides, LDL, VLDL and decreased HDL. The molecular mechanisms of abnormal lipid profiles in lupus patients currently are not properly understood. In this study, we generated mice that has lupus dyslipidemia on chow diet and studied the pathways that are responsible for increased cholesterol and triglycerides in plasma.
Materials and Methods:
LDLr/ and Fas/ (lpr/lpr) mice on the B6 background were purchased from the Jackson Laboratories (Bar Harbor, ME). These mice were interbred to produce mice homozygous for both LDLr-/- and lpr confirmed by PCR genotyping. LDLr/(LDLr) and LDLr-/-lpr-/- (LDLrLpr) mice were fed on chow diet. Thirteen female mice from each group were sacrificed at the age 2428 weeks.
LDLrLpr mice developed a lupus phenotype demonstrated by autoantibody production (ANA, anti-dsDNA, anti-sm, anti-cardiolipin antibodies), increased body weight, splenomegaly, hepatomegaly, and generalized lymphadenopathy compared to LDLr mice. LDLrLpr mice had a significantly increased proteinuria score (1.5±0.2 vs. 1.1±0.06; p<0.02) and renal histology score (1.8±0.4 vs. 0.4±0.1; p<0.004) compared to LDLr-/- mice. The lymphocyte population in the spleen measured by flow cytometry resulted in significantly increased CD4+Tcells (21% vs. 16%; p<0.003), double negative T cells (59% vs. 26%; p<0.001), and CD138+ plasma cells (12% vs. 0.4%; p<0.001) and decreased CD8+Tcells (6% vs. 14%; p<0.001) in LDLrLpr mice compared to LDLr mice similar to human lupus. Lipid analyses in LDLrLpr mice compared to LDLr mice on chow diet demonstrated significantly elevated total cholesterol (mg/dl) (347.0 ± 31.65 vs. 220.9 ± 8.235; p<0.0008), triglycerides (118.8 ± 18.51 vs. 42.85 ± 3.665; p<0.0005), VLDL (66.85 ± 17.54 vs. 3.385 ± 0.4875; p<0.0014) and LDL cholesterol (214.9 ± 22.22 vs. 148.1 ± 8.049; p<0.0093) without significant difference in HDL level. The increased level in triglycerides due to increased triglyceride secretion as measured by triton block experiment and decreased hepatic and lipoprotein lipase activity in LDLrLpr mice. The increased plasma cholesterol is due to increased cholesterol synthesis and decreased fatty oxidation in liver in LDLrlpr mice as measured by gene expression analysis.
Increased cholesterol synthesis, decreased fatty acid oxidation, increased triglyceride secretion and decreased lipase activity are the molecular mechanisms of dyslipidemia in lupus mice.
To cite this abstract, please use the following information:
Mishra, Nilamadhab, Yan, Kailin, Cao, Qiang; Molecular Mechanisms of Lupus Dyslipidemia in Mice. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :438