The free fatty acid receptor FFAR4 regulates CD36 protein expression through a PCSK9-dependent pathway - The FFAR4–PCSK9–CD36 regulatory axis –

Brown adipose tissue plays a crucial role in systemic energy homeostasis by taking up and metabolizing large amounts of fatty acids. The fatty acid sensor FFAR4 and the transporter CD36 are key proteins in this process, but their functional interaction has not been fully characterized. In this study, we generated FFAR4-deficient mouse brown adipocyte cell lines and found that this chronic deficiency of FFAR4 led to a compensatory increase in CD36 mRNA expression. However, subsequent experiments using transient overexpression systems revealed a distinct, rapid post-translational regulation mechanism: FFAR4 activation markedly reduced CD36 protein levels. In addition, we identified the secreted enzyme PCSK9 as a key mediator. We demonstrated that FFAR4 promotes the maturation and enhances the secretion of PCSK9, an effect driven by a promotion of its transcription. The secreted PCSK9 then induced the degradation of CD36 through both autocrine and paracrine pathways. This newly identified FFAR4–PCSK9–CD36 axis appears to function as a sophisticated negative feedback loop, or “emergency brake,” protecting brown adipocytes against excessive fatty acid uptake and lipotoxicity. These findings reveal a critical mechanism for the maintenance of lipid homeostasis and identify a promising new therapeutic target for metabolic diseases. • FFAR4 activation rapidly reduces CD36 protein through a PCSK9-dependent pathway. • FFAR4 promotes PCSK9 transcription, maturation, and secretion. • Secreted PCSK9 degrades CD36 via an autocrine/paracrine mechanism. • The FFAR4–PCSK9–CD36 axis protects brown adipocytes from lipotoxicity.