Estrogen-induced alterations in lipoprotein metabolism in autoimmune MRL/lpr mice

Estrogen replacement therapy has been demonstrated to shift the lipoprotein profile toward a less atherogenic one with concomitant increases in HDL and reductions in LDL cholesterol and serum triglycerides. Estrogen, however, has also been implicated in playing a significant role in autoimmune disease and may be involved with disease incidence and progression. The MRL/lpr mouse strain represents an autoimmune disease model with features resembling systemic lupus erythematosus including high-titer autoantibodies, glomerulonephritis, and vasculitis. In the present study, the effects of estrogen treatment on serum lipoprotein profiles were investigated by fast protein liquid chromatography in female MRL/lpr mice, in the MRL/++ strain with a milder form of disease, and in control Balb/c mice. Treatment of MRL/lpr mice for periods of 1 week or longer with pharmacologic doses of estrogen resulted in a significant increase in the amount of cholesterol carried on LDL particles. The up to eightfold increase in LDL cholesterol was less significant in the MRL/++ or Balb/c mice. Maximal increases were observed at 1 to 2 mg/kg of estrogen agonists, and the effect on LDL cholesterol increases was inhibited by tamoxifen. The HDL-to-LDL shift in cholesterol observed in estrogen-treated autoimmune mice correlated with an increase in apolipoprotein E, primarily on larger HDL particles. In addition to the increase in LDL cholesterol, hormonal treatment also resulted in a shift in triglycerides from the VLDL to the LDL fraction in both normal and autoimmune mice. These results suggest that pharmacologic doses of estrogen may contribute to cardiovascular disease progression by shifting the relative distribution of cholesterol from HDL to LDL in this murine model of lupus.