Hee-Hoon Kim¹, Young-Ri Shim¹, Sung Eun Choi¹, Myung-Ho Kim^1,2, Giljae Lee³, Hyun Ju You³, Won-Mook Choi^1,4, Keungmo Yang¹, Tom Ryu¹, Kyurae Kim¹, Min Jeong Kim¹, Chaerin Woo¹, Katherine Po Sin Chung¹, Song Hwa Hong¹, Hyuk Soo Eun^1,5, Seok-Hwan Kim⁶, GwangPyo Ko³, Jong-Eun Park⁷, Bin Gao ⁸, Won Kim⁹ and Won-Il Jeong ¹

¹Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea. 
²Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, MA, USA. 
³Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul 08826, Republic of Korea. 
⁴Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea. 
⁵Department of Internal Medicine, Chungnam National University, College of Medicine, Daejeon 35015, Republic of Korea. 
⁶Department of Surgery, Chungnam National University, College of Medicine, Daejeon 35015, Republic of Korea. 
⁷Single-Cell Medical Genomics Laboratory, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea. 
⁸Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD 20892, USA. 
⁹Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul 07061, Republic of Korea. 

Corresponding Authors: Won Kim and Won-Il Jeong

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.