Journal Article

Catecholamine induces Kupffer cell apoptosis via growth differentiation factor 15 in alcohol-associated liver disease

Kim, Hee-Hoon, Ryu, Tom, Hong, Song Hwa, Yang, Keungmo, Woo, Chaerin, Kim, Myung-Ho, Kim, Kyurae, Ko, GwangPyo, Gao, Bin, You, Hyun Ju, Jeong, Won-Il, Kim, Min Jeong, Kim, Won, Chung, Katherine Po Sin, Shim, Young-Ri, Lee, Giljae, Eun, Hyuk Soo, Park, Jong-Eun, Choi, Won-Mook, Kim, Seok-Hwan, Choi, Sung Eun

2023

Overview

Chronic alcohol consumption often induces hepatic steatosis but rarely causes severe inflammation in Kupffer cells (KCs) despite the increased hepatic influx of lipopolysaccharide (LPS), suggesting the presence of a veiled tolerance mechanism. In addition to LPS, the liver is affected by several gut-derived neurotransmitters through the portal blood, but the effects of catecholamines on KCs have not been clearly explored in alcohol-associated liver disease (ALD). Hence, we investigated the regulatory roles of catecholamine on inflammatory KCs under chronic alcohol exposure. We discovered that catecholamine levels were significantly elevated in the cecum, portal blood, and liver tissues of chronic ethanol-fed mice. Increased catecholamines induced mitochondrial translocation of cytochrome P450 2E1 in perivenous hepatocytes expressing the β2-adrenergic receptor (ADRB2), leading to the enhanced production of growth differentiation factor 15 (GDF15). Subsequently, GDF15 profoundly increased ADRB2 expression in adjacent inflammatory KCs to facilitate catecholamine/ADRB2-mediated apoptosis. Single-cell RNA sequencing of KCs confirmed the elevated expression of Adrb2 and apoptotic genes after chronic ethanol intake. Genetic ablation of Adrb2 or hepatic Gdf15 robustly decreased the number of apoptotic KCs near perivenous areas, exacerbating alcohol-associated inflammation. Consistently, we found that blood and stool catecholamine levels and perivenous GDF15 expression were increased in patients with early-stage ALD along with an increase in apoptotic KCs. Our findings reveal a novel protective mechanism against ALD, in which the catecholamine/GDF15 axis plays a critical role in KC apoptosis, and identify a unique neuro-metabo-immune axis between the gut and liver that elicits hepatoprotection against alcohol-mediated pathogenic challenges. Liver disease: Pathways converge to avert alcohol-induced damage The interplay between neurochemical, metabolic, and immunological processes helps to control inflammatory damage to the liver arising from chronic alcohol consumption. Catecholamine is a neurotransmitter that is also produced outside the brain, including by microbiome in the gut. Researchers in South Korea led by Won-Il Jeong of the Korea Advanced Institute of Science & Technology, Daejeon, and Won Kim at Seoul National University have shown how this molecule contributes to the protective response against alcohol-induced liver damage. Mice routinely dosed with alcohol produced high levels of catecholamine in their gut, which generated a metabolic stress response in a subset of liver cells. These stressed liver cells subsequently transmit signals to certain immune cells within the liver, causing those cells to self-destruct and thereby averting a damaging inflammatory response that could otherwise accelerate disease progression.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,생화학분자생물학회
• Subject: 13/2 / 13/31 / 13/51 / 13/95 / 14/1 / 38/77 / 38/91 / 631/80/82/23 / 64/110 / 64/60 / 692/308/575 / 692/420/256/2515 / 692/699/1503/1607/1608 / 82/80 / Adrenergic receptors / Alcohol / Alcohol use / Animals / Apoptosis / Biomedical and Life Sciences / Biomedicine / Blood / Catecholamines / Cecum / Cell differentiation / Cellular stress response / Cytochrome P450 / Drug tolerance / Ethanol / Ethanol - metabolism / Ethanol - toxicity / Fatty liver / Growth Differentiation Factor 15 - metabolism / Growth Differentiation Factor 15 - pharmacology / Hepatocytes / Immunological tolerance / Inflammation / Inflammation - metabolism / Kupffer cells / Kupffer Cells - metabolism / Lipopolysaccharides / Lipopolysaccharides - metabolism / Liver - metabolism / Liver diseases / Liver Diseases, Alcoholic - genetics / Liver Diseases, Alcoholic - metabolism / Medical Biochemistry / Metabolism / Mice / Microbiomes / Mitochondria / Molecular Medicine / Neurotransmitters / Steatosis / Stem Cells / 생화학