Introduction of Hepatic Metabolism in Ischemic Stroke

Local brain injury and neurological dysfunction are direct effects of acute ischemic stroke (AIS). As the immune system, the hypothalamic-pituitary-adrenal system, and the autonomic nervous system are manipulated during acute cerebral ischemia, it influences systems across the peripheral organs, research has shown over the past few years. The correlation affects brain function as a whole and stroke prognosis. For liver and brain, as central metabolic organs, there is their own language for delivering metabolic messages.

The liver plays a crucial role in post-stroke responses, contributing to immunosuppression and stress-induced hyperglycemia. Additionally, the liver increases ketogenesis and glutathione production to help reduce inflammation and oxidative stress in stroke. In conclusion, studying the relationship between ischemic stroke and hepatic metabolism can help explore potential liver-related targets for stroke treatment.

Fig.1. The brain and liver are related to each other in the pathogenesis of many diseases. (Tian, et al., 2022)

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Hepatic Immune Response and Ischemic Stroke

Systemic inflammation

After AIS, brain-derived cytokines and damage-associated molecular patterns (DAMPs) reach the bloodstream and trigger innate immune cells to cause systemic inflammation.

Autonomic and neuroendocrine responses

AIS causes sympathetic activation of the adrenal medulla and adrenal cortex through the hypothalamic-pituitary-adrenal (HPA) axis, which releases catecholamines and glucocorticoids.

Hepatic invariant natural killer T (iNKT) cells

iNKT cells respond specifically to ischemic brain injury following middle cerebral artery occlusion (MCAO). They recognize CD1d-presented lipid antigens but are activated by noradrenergic neurotransmission rather than direct ligand recognition. Stroke-induced decreased crawling activity of iNKT cells and increased production of the anti-inflammatory cytokine interleukin (IL)-10 ultimately promote immunosuppression and postischemic infection. Thus, both stimulation of iNKT cells and blockade of noradrenergic neurotransmission may prevent infection after MCAO.

Vagus nerve activity

More parasympathetic responses after stroke are another immunosuppressive factor. Cytokines pierce afferent vagus nerve fibers, which sets in motion a cholinergic anti-inflammatory signal. Blocking this signaling can ameliorate immunosuppression following cerebral ischemia, and vagus nerve stimulation can inhibit liver tumor necrosis factor (TNF) production and reduce infarct size in MCAO models.

Glucose Metabolism and Ischemic Stroke

Diabetes is one of the main risk factors for stroke. Since the liver is one of the major metabolic organs, stroke hyperglycemia can happen at this site. Sympathetic overactivity and liver inflammation result in stroke-induced hyperglycemia, insulin resistance, and glycogenolysis. Acute ischemic brain injury leads to increased fasting glucose and insulin with dysfunctional hepatic insulin signaling in rodents.

Ketogenesis is driven by hepatic gluconeogenesis following stroke. Ketones-liver hydroxybutyrate (BHB) in particular- could protect the brain from these as a substitute energy source.

Glutathione and Ischemic Stroke

In ischemic stroke, ROS are produced and excreted in the wrong balance, resulting in oxidative stress. Markers of oxidative stress are elevated in the brain and the peripheral tissues. GSH is a key antioxidant tripeptide (c-L-glutamyl-L-cysteinylglycine). GSH levels are reduced in stroke patients. In animal models, GSH levels are decreased in both the brain and liver after ischemia/reperfusion (I/R) injury.

The liver is the primary site of glutathione production, and hepatic glutathione release determines plasma levels. In situations of severe oxidative stress, peripheral GSH could enhance antioxidative activity in the ischemic brain. Intravenous injection or oral GSH can restore decreased GSH and cysteine levels in the brain after experimental stroke. Alternatively, targeting hepatic GSH synthesis may be a way to increase GSH and cysteine availability to counteract peripheral and cerebral oxidative stress.

Lipid Metabolism and Ischemic Stroke

The regulation of lipid metabolism is a crucial function of the liver, and this process is disrupted by AIS. Enhancing liver low-density lipoprotein (VLDL) formation by hosphoethanolamine N-methyltransferase (PEMT) following cerebral ischemia. Such a strategy could raise plasma triglyceride levels and ameliorate stress-related hyperglycemia by moving free fatty acids from -oxidation to hepatic lipogenesis. And the liver's lipoproteins are high in PC, which keeps the cell membrane intact and working properly. When we have ischemic brain damage, the cell membrane can be attacked by proteases, phospholipases, and lipid peroxidase.

Cytidine diphosphate (CDP-) choline is the intermediate for PC synthesis via the CDP-choline pathway, the other major route responsible for hepatic PC synthesis. Interestingly, CDP-choline, generically called citicoline, has been proposed as a treatment for ischemic stroke patients even though clinical trials have failed to show a positive effect on mortality and recovery.

1. Yang, X., et al. (2024). Metabolic Crosstalk between Liver and Brain: From Diseases to Mechanisms. International Journal of Molecular Sciences, 25(14), 7621.