Lipid influx enforces liver regeneration through the recruitment of CD36+ macrophages (scRNA-Seq and RNA-Seq)

The liver possesses a remarkable regeneration capacity under a wide variety of injury conditions, like partial hepatectomy (PHx) and over-dose acetaminophen (APAP) treatment. Macrophages, multitask at the wound site by facilitating wound debridement and producing chemokines, metabolites and growth factors, and consequently determine the balance between ongoing damage and repair following tissue injury. CD36, which is universally expressed in a wide variety of cells (i.e., macrophages, adipocytes, myocytes, enterocytes and hepatocytes), and serves as the predominant fatty acid uptake facilitator of the cells to uptake microenvironmentally enriched lipids in various settings. However, the role for macrophage CD36 in mediating lipid accumulation as well as the regeneration of liver post physiological or pathophysiological injury still remains largely unknown. Herein, by utilizing multiple seq-based methods, we found the transient lipid accumulation in injured livers post PHx or APAP treatment exerted fundamental impacts on hepatic immune remodeling and induced the recruitment of macrophages with high level of CD36 expression and excessive lipid accumulation which facilitate the regeneration of livers. CD36-mediated lipid influx in macrophages triggers the activation of IRE1a signaling pathways via intracellular ceramide accumulation to promote high levels of IL6 production to accelerate liver regeneration.