Bridging systemic metabolic dysfunction and Alzheimer's disease: the liver interface

Abstract

Alzheimer's disease (AD) is increasingly recognized as a systemic disorder with a substantial metabolic disorder component, where the liver significantly impacts the brain via the liver-brain axis. Key mechanisms include the liver's role in clearing peripheral β-amyloid (Aβ), the influence of hepatic enzymes and metabolites on cognitive decline, and the systemic effects of metabolic disorders on AD progression. Hepatokines, liver-secreted proteins including fibroblast growth factor (FGF)-21, selenoprotein P (SELENOP), Fetuin-A, Midbrain astrocyte-derived neurotrophic factor (MANF), apolipoprotein J (ApoJ), sex hormone-binding globulin (SHBG), Adropin and Angiopoietin-like protein 3 (ANGPTL3), could regulate insulin sensitivity, lipid metabolism, oxidative stress, immune responses, and neurotrophic support. These pathways are closely linked to core AD pathologies, including Aβ aggregation, tau hyperphosphorylation, neuroinflammation, oxidative stress and mitochondrial dysfunction. Lifestyle interventions, including exercise and dietary modifications, that regulate hepatokines expression may offer novel preventive and therapeutic strategies for AD. This review synthesizes current knowledge on the liver-brain crosstalk in AD, emphasizing the mechanistic role of liver in bridging metabolic dysfunction with neurodegeneration and underscores the diagnostic and therapeutic potential of hepatokines in addressing AD's complex pathology.

Keywords: Alzheimer’s disease; Hepatokines; Liver; Metabolic disorders; Metabolism.

Fig. 1

Interactions Between the Liver and Brain in Metabolic and Neurological Regulation. This figure illustrates the bidirectional communication between the liver and the CNS via metabolic and inflammatory pathways. Left Panel: The liver exerts systemic effects on the CNS through dysregulated metabolic processes and inflammatory mediators. Elevated liver enzyme activity, increased blood ammonia levels, aberrant hepatokine secretion, and an altered BCAAs to AAA ratio collectively contribute to BBB dysfunction, neuroinflammation, and neuronal degeneration. These pathological changes exacerbate CNS damage and cognitive decline. Right Panel: The brain modulates liver function through the autonomic nervous system. Sympathetic and parasympathetic innervation regulates hepatic glucose and lipid metabolism, while adrenal-mediated catecholamine release influences hepatic inflammatory responses. Furthermore, the liver plays an essential role in clearing Aβ peptides from circulation, mitigating their accumulation in the brain and reducing neurotoxicity

Fig. 2

Roles of Hepatokines in Alzheimer’s Disease. This figure summarizes the multifaceted roles of hepatokines in the pathophysiology of AD, highlighting their contributions to inflammation, oxidative stress, and neuronal function. FGF-21 inhibits tau and Aβ polymerization, regulates microglial polarization to suppress inflammation, and protects neurons from necrosis and apoptosis. SELENOP delivers selenium to the brain, mitigating oxidative stress, inhibiting tau phosphorylation, and suppressing M1 microglial activation to regulate neuroinflammation. Fetuin-A reduces mitochondrial oxidative stress, prevents neuronal apoptosis, and inhibits the release of pro-inflammatory factors. By modulating testosterone, SHBG enhances mitochondrial function, which in turn reduces oxidative stress and inflammation. Adropin strengthens the BBB, facilitates glucose metabolism, and reduces oxidative damage. ApoJ aids in Aβ clearance, boosts microglial phagocytosis, and alleviates neuroinflammation. ANGPTL3, interacting with ANGPTL8, regulates lipid metabolism and contributes to neuroinflammation and Aβ dysregulation. Lastly, MANF alleviates ER stress, suppresses oxidative damage, and promotes anti-inflammatory microglial activity, underscoring its neuroprotective potential

Fig. 3

The bridging role of hepatokines in AD and metabolic disorders. This figure highlights the central role of hepatokines in linking AD and metabolic disorders through mechanisms involving IR, neuroinflammation, and oxidative stress. In IR, FGF-21 binds to KLB receptors to promote GLUT-1-mediated glucose uptake and alleviate IR, while ANGPTL3 increases blood TG levels by inhibiting LPL activity. SELENOP suppresses AMPK phosphorylation, reducing ACC phosphorylation, thereby enhancing fatty acid synthesis and exacerbating IR. Reduced levels of Fetuin-A attenuate TGFBR signaling in pancreatic islets, inhibit SMAD2/3 phosphorylation, and regulate insulin secretion. SHBG enhances IR by regulating glucose transporter expression through the cAMP/PKA/CREB1 signaling pathway. In neuroinflammation, ApoJ stimulates microglia, enhancing reactive nitrogen intermediates and pro-inflammatory cytokines like TNF-α. Concurrently, Fetuin-A facilitates macrophage migration and polarization via the JNK-c-Jun-IFN-γ–JAK2–STAT1 pathway, intensifying adipose tissue inflammation. Conversely, FGF-21 inhibits NF-κB signaling via the TLR4 receptor, and MANF provides neuroprotection by suppressing NF-κB during ER stress and activating the AKT/GSK3β-Nrf2 axis. In oxidative stress, FGF-21 activates FGFR1 to destabilize the Keap1-Nrf2 complex, enabling Nrf2 to initiate the antioxidant response, while SELENOP binds to LRP-1 to maintain Gpx4 activity and prevent lipid peroxidation