Plasma lipoproteins are required for both basal and stress-induced adrenalglucocorticoid synthesis and protection against endotoxemia in mice.

摘要

Lipoprotein-associated cholesterol has been suggested to make a significantcontribution to adrenal steroidogenesis in vivo. To determine whetherlipoproteins indeed contribute to optimal adrenal steroidogenesis in mice, in thecurrent study we have determined the effect of relative lipoprotein deficiency onadrenal steroidogenesis in C57BL/6 wild-type mice. Feeding C57BL/6 mice thelipid-lowering drug probucol (0.25% wt/wt) for 2 wk induced a 90% decrease inplasma high-density lipoprotein (HDL) cholesterol levels and a 77% reduction inlow-density lipoprotein (LDL) cholesterol levels. Neutral lipid stores weredepleted upon probucol treatment specifically in the glucocorticoid-producingzona fasciculata of the adrenal, leading to a 44% decreased plasma corticosteronelevel under basal conditions. Exposure to lipopolysaccharide (LPS) induced a 37% increase in the adrenal uptake of HDL cholesteryl esters. Probucol-treated micecould induce only a relatively minor corticosterone response upon a LPS challengecompared with controls, which coincided with an approximately twofold increasedhepatic expression level of interleukin-6 and tumor necrosis factor (TNF)alpha and an89% higher TNFalpha response in plasma. Furthermore, a compensatory two- to fivefold upregulation of LDL receptor (cholesterol uptake) and HMG-CoA reductase(cholesterol synthesis) expression was noticed in the adrenals ofprobucol-treated mice. In conclusion, we have shown that lipoprotein deficiencyin mice as a result of probucol feeding is associated with decreased adrenalcortex cholesterol levels, a lower basal and stress-induced plasma glucocorticoidlevel, and an increased susceptibility to LPS-induced inflammation. Therefore, itis suggested that plasma lipoproteins are required for optimal adrenalsteroidogenesis and protection against endotoxemia in mice.