Reversing liver sinusoidal endothelial aging restores clearance of amyloid-beta and LDL
- 1Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, Los Angeles, California, USA
Abstract
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, 2 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 low-density lipoprotein receptor-related protein-1 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.
Related
- AICAR attenuates senescence-associated phenotypic remodeling of liver sinusoidal endothelial cells via the AMPK–SIRT1/p53 axis in CCl₄-induced liver fibrosis
- Association between clozapine-induced hypertriglyceridemia and defenestration of liver sinusoidal endothelial cells.
- Lipotoxicity Amplifies IL‐6 Trans‐Signaling in Sinusoidal Endothelial Cells to Promote Endotheliopathy and Liver Injury
- Toward selective amyloid clearance through rational nanomedicine design
- Progesterone restores mitochondrial bioenergetic function in streptozotocin- and amyloid-β-challenged HT-22 hippocampal cells: An in vitro model of Alzheimer's disease
BibTeX
@article{leve2026reversing,
title = {{Reversing liver sinusoidal endothelial aging restores clearance of amyloid-beta and LDL}},
author = {Sam J. de Leve and Xiangdong Wang and Helia Alavifard and Lily Dara and Laurie D. DeLeve},
journal = {The Journal of Biological Chemistry},
year = {2026},
month = sep,
doi = {10.1016/j.jbc.2026.113608},
url = {https://doi.org/10.1016/j.jbc.2026.113608},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Reversing liver sinusoidal endothelial aging restores clearance of amyloid-beta and LDL
AU - Sam J. de Leve
AU - Xiangdong Wang
AU - Helia Alavifard
AU - Lily Dara
AU - Laurie D. DeLeve
PY - 2026
DA - 2026/09/26
JO - The Journal of Biological Chemistry
DO - 10.1016/j.jbc.2026.113608
UR - https://doi.org/10.1016/j.jbc.2026.113608
AB - 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, 2 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 low-density lipoprotein receptor-related protein-1 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.
SN - 0021-9258
SN - 1083-351X
ER -