The two key results are as follows: (1) studies of cell surface binding and cell-free protein–protein interactions indicated that PA directly bound to MD2, supporting a mechanism of direct PA (and possibly other SFAs) binding to MD2 to activate TLR4 signalling, and (2) Blockade of MD2 prevented production of pro-inflammatory molecules in myocardial tissue, cardiac tissue remodelling and cardiac dysfunction in mice with hyperlipidemia and/or obesity. Here, TLR4 is linked to hyperlipidemia.