Metabolic Crosstalk between Liver and Brain: From Diseases to Mechanisms

Abstract

Multiple organs and tissues coordinate to respond to dietary and environmental challenges. It is interorgan crosstalk that contributes to systemic metabolic homeostasis. The liver and brain, as key metabolic organs, have their unique dialogue to transmit metabolic messages. The interconnected pathogenesis of liver and brain is implicated in numerous metabolic and neurodegenerative disorders. Recent insights have positioned the liver not only as a central metabolic hub but also as an endocrine organ, capable of secreting hepatokines that transmit metabolic signals throughout the body via the bloodstream. Metabolites from the liver or gut microbiota also facilitate a complex dialogue between liver and brain. In parallel to humoral factors, the neural pathways, particularly the hypothalamic nuclei and autonomic nervous system, are pivotal in modulating the bilateral metabolic interplay between the cerebral and hepatic compartments. The term "liver-brain axis" vividly portrays this interaction. At the end of this review, we summarize cutting-edge technical advancements that have enabled the observation and manipulation of these signals, including genetic engineering, molecular tracing, and delivery technologies. These innovations are paving the way for a deeper understanding of the liver-brain axis and its role in metabolic homeostasis.

Keywords: autonomic nervous system; brain; hepatokines; interorgan crosstalk; liver; metabolism; metabolites.

Figure 1

The brain and liver are related to each other in the pathogenesis of many diseases. HE, hepatic encephalopathy; AHCD, acquired hepatocerebral degeneration; AD, Alzheimer’s disease; TBI, traumatic brain injury; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; Aβ, amyloid-β; APOE4, apolipoprotein E4. This figure was created using Figdraw.

Figure 2

Hepatokine signaling from liver to brain. (a) FGF21, as a hepatokine, acts on the hypothalamus to regulate the HPA axis, GABA-containing neurons, and sympathetic nerve activity. (b) GDF15 is mainly secreted by the liver under injury or metabolic stress as an endocrine signal that initiates emergency neural circuits. (c) Both peripheral and central ANGPTL8 administration reduces c-Fos positive neuronal expression in the DMH and alters NPY activity to reduce food intake. ANGPTL8 is widely expressed in the PVN, DMH, VMH, and ARC. (d) LEAP2 serves as a liver-derived antagonist of the ghrelin receptor, and its secretion is suppressed by fasting. (e) Stress triggers the release of LCN2 from the liver, which in turn contributes to the development of anxiety-like behavior in mice. FGF21, fibroblast growth factor 21; PVN, paraventricular nucleus; SCN, suprachiasmatic nucleus; HPA, hypothalamic–pituitary–adrenal; AP, area postrema; NTS, nucleus of the solitary tract; RET, rearranged during transfection; GFRAL, glial-derived neurotropic factor receptor-alike; DMH, dorsal medial nucleus; VMH, ventral medial nucleus; ARC, arcuate nucleus; GHSR, growth hormone secretagogue receptor; SLC22A17, solute carrier family 22 member 17; BBB, blood–brain barrier; GDF15, growth differentiation factor; ANGPTL8, angiopoietin-like proteins; LEAP2, liver-enriched antimicrobial peptide-2; LCN2, lipocalin-2.

Figure 3

Distant communicating pathways, such as hormonal, neuronal, metabolic, and other factors, across liver-gut–brain axis. ANS, autonomic nervous system; ENS, enteric nervous system; SCFAs, short-chain fatty acids; BAs, bile acids. Part of this figure was drawn using materials from vecteezy.com, accessed on 20 May 2024.

Figure 4

Nerve fiber connections between the brain and the liver. NTS, nucleus of the solitary tract; DMV, dorsal motor nucleus of the vagus; IML, intermediolateral column. Part of this figure was drawn using materials from smart.servier.com, accessed on 3 February 2024.

Figure 5

Strategies to observe crosstalk between liver and brain, including tracing strategies to neural circuits and hormonal molecules, and some molecular delivery techniques from liver to brain. SORT-LNPs, selective organ targeting-lipid nanoparticles; GalNAc, N-acetylgalactosamine coupling; ASGPR, Asialoglycoprotein receptor. Part of this figure was drawn using materials from https://www.figdraw.com/#/, accessed on 20 May 2024.