Inhibiting peripheral serotonin activates liver AMPK and reduces monocyte-derived macrophages and fibrosis
Battsetseg Batchuluun1, Tinne Thoné2, Andre Djalalvandi1
1Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON, Canada.
Abstract:
Monocyte-derived liver macrophages are critical in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, but their recruitment mechanisms remain unclear. Serotonin (5-hydroxytryptamine [5HT]) is a conserved monoamine synthesized by tryptophan hydroxylase 1 (Tph1) in peripheral tissues and Tph2 in the brain. We show that, in mice housed at thermoneutrality and fed a high-fat, high-fructose diet, inhibition of peripheral serotonin (pe5HT) through genetic deletion of Tph1 prevents MASH independent of reduction in body weight. Liver flow cytometry and single-nucleus sequencing showed reduced pro-inflammatory Ly6Chigh monocytes, monocyte-derived Kupffer cells (moKCs), and lipid-associated macrophages (LAMs) in Tph1 knockout (KO) mice. Tph1 deletion also decreased circulating monocytes, specifically Ly6Chigh monocytes. A single 5HT injection increased Ly6Chigh monocytes, while Tph1 KO mice had reduced monocytes without affecting bone marrow monocytes. Mechanistically, serotonin inhibition increases liver AMP-activated protein kinase (AMPK) activity, and this is important for reducing CCL2 and monocyte recruitment. These findings link two ancient energy sensors, 5HT and AMPK, with obesity-associated liver fibrosis.
Insights
Inhibition of peripheral serotonin (5-hydroxytryptamine) prevents metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis by reducing monocyte recruitment. This highlights serotonin and AMPK
Area of Science:
- Hepatology
- Immunology
- Metabolic Diseases
Background:
- Monocyte-derived liver macrophages drive metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis.
- Mechanisms of monocyte recruitment in MASH remain poorly understood.
Purpose of the Study:
- To investigate the role of peripheral serotonin (5-hydroxytryptamine) in monocyte recruitment and MASH pathogenesis.
- To explore the link between serotonin, AMP-activated protein kinase (AMPK), and liver fibrosis.
Main Methods:
- Utilized Tph1 knockout mice fed a high-fat, high-fructose diet at thermoneutrality.
- Employed liver flow cytometry and single-nucleus sequencing to analyze immune cell populations.
- Assessed the impact of serotonin (5HT) injection on monocyte levels.
Main Results:
- Genetic deletion of Tph1, inhibiting peripheral serotonin, prevented MASH development independently of body weight changes.
- Tph1 knockout mice exhibited reduced pro-inflammatory Ly6Chigh monocytes, Kupffer cells, and lipid-associated macrophages.
- Serotonin inhibition increased liver AMPK activity, leading to decreased CCL2 and reduced monocyte recruitment.
Conclusions:
- Peripheral serotonin signaling is a critical driver of monocyte recruitment in MASH.
- Targeting peripheral serotonin offers a potential therapeutic strategy for MASH and liver fibrosis.
- Serotonin and AMPK represent interconnected energy sensors involved in obesity-associated liver disease.
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