Proposed model for the role of SR-BI in modulating platelet reactivity. (A) Normolipidemia. Under normolipidemic conditions the platelet count and cholesterol content remain normal irrespective of whether platelets express SR-BI. Note that SR-BI^/− platelets have reduced responsiveness to high concentrations of soluble agonists relative to wild-type (WT) controls. (B) Hyperlipidemia. In the absence of SR-BI expression by steroidogenic tissues (principally the liver), there is reduced cholesterol uptake from the circulation, leading to hyperlipidemia. The severe hyperlipidemia in SR-BI^−/− results in thrombocytopenia and an increased platelet cholesterol content irrespective of whether platelets express SR-BI. Under hyperlipidemic conditions, SR-BI^−/− platelets have increased responsiveness to PAR4 agonists, but a paradoxical hyporesponsive to other agonists. Note that WT platelets are hyperresponsive to all agonists in the presence of hyperlipidemia.