Reversing liver sinusoidal endothelial aging restores clearance of amyloid-beta and LDL.

In healthy liver, large macromolecules pass freely into the space of Disse through liver sinusoidal endothelial cell (LSEC) fenestration. In aging, LSEC fenestration is largely lost (pseudocapillarization). We hypothesized that restoring aged LSECs' fenestration would enhance passage into the space of Disse of large-diameter (>50 nm) triglyceride-rich lipoproteins to which the majority of circulating amyloid-beta is bound and permit hepatocyte uptake of amyloid-beta: in aged rats, two weeks of the soluble guanylate cyclase activator cinaciguat restored fenestration; circulating amyloid-beta 40 levels halved, returning to levels found in young rats. Surprisingly, cinaciguat also reversed age-related increases in LDL (a smaller, 20-30 nm diameter lipoprotein), which crosses the sinusoidal endothelial barrier even when LSECs are defenestrated. We therefore investigated additional mechanisms by which LSECs promote hepatocyte clearance. Whereas primary hepatocytes had minimal uptake of amyloid-beta 40 or LDL, hepatocytes cultured in young rat LSEC conditioned medium retained their uptake function. Aged rat LSEC conditioned medium did not facilitate hepatocyte amyloid-beta 40 and LDL uptake but treating aged rats with cinaciguat restored aged rat LSECs paracrine signaling. We discovered that heparin-binding epidermal growth factor-like growth factor (HB-EGF) mediates this LSEC-hepatocyte interaction and that HB-EGF is synthesized but not secreted by aged rat LSECs; cinaciguat treatment restores aged LSECs' HB-EGF secretion. Treatment reversed age-associated loss of LDLR and LRP1 surface expression in rat hepatocytes. This study identifies a candidate therapy to address age-related increases in circulating amyloid-beta and LDL and elucidates an intercellular crosstalk mechanism that governs these phenomena.