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

[Author] 
Hee-Hoon Kim1 , Young-Ri Shim1 , Sung Eun Choi1 , Myung-Ho Kim1,2, Giljae Lee3 , Hyun Ju You3 , Won-Mook Choi1,4, Keungmo Yang1 , Tom Ryu1 , Kyurae Kim1 , Min Jeong Kim1 , Chaerin Woo1 , Katherine Po Sin Chung1 , Song Hwa Hong1 , Hyuk Soo Eun1,5, Seok-Hwan Kim6 , GwangPyo Ko3 , Jong-Eun Park7 , Bin Gao 8 , Won Kim9 and Won-Il Jeong 1

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

[Journal] 
Experimental & Molecular Medicine volume 55, pages158–170 (2023)

[Abstract]
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.