Peripheral amyloid-β clearance mediates cognitive impairment in non-alcoholic fatty liver disease

Background: Non-alcoholic fatty liver disease (NAFLD) is a prevalent risk factor for cognitive impairment. Cerebral Amyloid-β (Aβ) accumulation, as an important pathology of cognitive impairment, can be caused by impaired Aβ clearance in the periphery. The liver is the primary organ for peripheral Aβ clearance, but the role of peripheral Aβ clearance in NAFLD-induced cognitive impairment remains unclear.

Methods: We examined correlations between NAFLD severity, Aβ accumulation, and cognitive performance in female Sprague-Dawley rats. The impact of NAFLD on hepatic Aβ clearance and the involvement of low-density lipoprotein receptor-related protein 1 (LRP-1) were assessed in rat livers and cultured hepatocytes. Additionally, a case-control study, including 549 NAFLD cases and 549 controls (782 males, 316 females), investigated the interaction between NAFLD and LRP-1 rs1799986 polymorphism on plasma Aβ levels.

Findings: The severity of hepatic steatosis and dysfunction closely correlated with plasma and cerebral Aβ accumulations and cognitive deficits in rats. The rats with NAFLD manifested diminished levels of LRP-1 and Aβ in liver tissue, with these reductions inversely proportional to plasma and cerebral Aβ concentrations and cognitive performance. In vitro, exposure of HepG2 cells to palmitic acid inhibited LRP-1 expression and Aβ uptake, which was subsequently reversed by a Peroxisome Proliferator-activated Receptor α (PPARα) agonist. The case-control study revealed NAFLD to be associated with an increment of 8.24% and 10.51% in plasma Aβ40 and Aβ42 levels, respectively (both P < 0.0001). Moreover, the positive associations between NAFLD and plasma Aβ40 and Aβ42 levels were modified by the LRP-1 rs1799986 polymorphism (P for interaction = 0.0017 and 0.0015, respectively).

Interpretation: LRP-1 mediates the adverse effect of NAFLD on peripheral Aβ clearance, thereby contributing to cerebral Aβ accumulation and cognitive impairment in NAFLD.

Funding: Major International (Regional) Joint Research Project, National Key Research and Development Program of China, National Natural Science Foundation of China, and the Angel Nutrition Research Fund.

Aβ accumulation; Cognitive impairment; LRP-1; NAFLD; Peripheral Aβ clearance; rs1799986 polymorphism.