SR-BI (Scavenger Receptor BI), not LDL (Low-Density Lipoprotein) receptor, mediates adrenal stress response - Brief report

Objective: Adrenal gland secretes stress-induced glucocorticoids (iGCs) to coping with stress. Previous study showed that SR-BI (scavenger receptor BI) null (SR-BI^-/-) mice failed to generate iGC in stress conditions, suggesting that SR-BI-mediated cholesterol uptake from HDL (high-density lipoprotein) is a key regulator for iGC production. However, the LDL (low-density lipoprotein)/LDLr (LDL receptor) pathway can also provide cholesterol for iGC synthesis, but rodents have limited LDL levels in circulation. Here, we generated SR-BI^-/-ApoBtg (apolipoprotein B transgenic) mice with normal LDL levels in circulation to determine the relative contribution of the HDL/SR-BI and LDL/LDLr pathways to iGC production in stress conditions. Approach and Results: To obtain mouse models with normal LDL levels, SR-BI^-/- mice were bred to ApoBtg mice. Then, the F1 SR-BI±ApoBtg mice were backcrossed to SR-BI^-/- to obtain SR-BI^-/-ApoBtg, SR-BI^-/-ApoBwt (apolipoprotein B wild type), and SR-BI^+/+ApoBtg mice. We first examined the lipoprotein profile, which shows a 6.5-fold increase in LDL levels in SR-BI^-/-ApoBtg mice compared with SR-BI^-/-ApoBwt mice. Then, we induced stress with adrenocorticotropic hormone and cecal ligation and puncture. One hour after adrenocorticotropic hormone stimulation, SR-BI^+/+ApoBtg control mice produced iGC (14.9-fold), but both SR-BI^-/-ApoBwt and SR-BI^-/-ApoBtg showed no iGC production (P<0.001). Three hours after cecal ligation and puncture treatment, SR-BI^+/+ApoBtg control mice showed iGC production (6.4-fold), but both SR-BI^-/-ApoBwt and SR-BI^-/-ApoBtg mice showed no iGC production (P<0.001). Conclusions: SR-BI^-/-ApoBtg mice fail to produce iGC in stress conditions even though with restored LDL levels in circulation. These findings clarify that the HDL/SR-BI, not LDL/LDLr, pathway is responsible for iGC production in stress conditions.