Part I: Intestinal catecholamines drive inflammatory Kupffer cell apoptosis through hepatic growth differentiation factor 15In the early stage of alcoholic liver disease (ALD), activation of Kupffer cells (KCs) by gut-derived endotoxins such as lipopolysaccharide initiates the inflammatory response. Therefore, precise adaptation to microbiome perturbation is essential to maintain hepatic immunological homeostasis. In the liver, catecholamines produced by sympathetic innervations suppress hepatic macrophages, but persistent metabolic stress causes hepatic sympathetic neuropathy. However, alcoholic steatohepatitis (ASH) is developed in only 10 to 35 percent of patients with ALD, suggesting the presence of an efficient compensatory pathway that suppresses activation of KCs in ALD. Recent studies have been emphasized the roles and changes of gut microbiome in chronic alcohol consumption. Interestingly, gut microbiome could produce biologically active catecholamines, which may be delivered to the liver through portal blood. Here, by applying single-cell RNA-sequencing and in situ liver perfusion system, we unveiled how hepatic metabolism regulates inflammatory KCs by sensing catecholamines from portal blood both in mice and patients with ALD. We discovered that gut-derived catecholamines increased mitochondrial translocation of cytochrome P450 2E1 in β2-adrenergic receptor (ADRB2)-expressing perivenous hepatocytes, which enhanced growth differentiation factor 15 (GDF15) production by ethanol. Moreover, GDF15 profoundly increased ADRB2 expression of neighboring inflammatory KCs to facilitate catecholamine-mediated apoptosis. In genetic ablation of Adrb2 or hepatic Cyp2e1 or Gdf15, apoptotic inflammatory KCs were robustly decreased with GDF15 level, which exacerbated alcoholic liver inflammation and injury. Furthermore, catecholamine/GDF15/ADRB2 axis was enhanced in patients with the early phase of ALD compared to healthy subjects. Our findings reveal novel catecholamine-sensitive KCs regulated by hepatic GDF15 and identify a unique neuro-metabo-immune communication between the gut and liver that induces precise hepatoprotection to the challenges of alcohol-mediated pathogenic microbiome.Part II: Type II interferon governs obese adipocyte-hepatocyte proline/glutamine circuit to drive non-alcoholic steatosisHepatic de novo lipogenesis is one of the important metabolic changes in the development of non-alcoholic steatosis. Recent studies have been highlighted the metabolic role of type II interferon, interferon-γ (IFN-γ), and perturbed in glutamine metabolism in visceral adipose tissue in the development of obesity. Although strong relationship between obesity and non-alcoholic hepatic steatosis has been reported, how visceral adipose tissue-derived IFN-γ or amino acids regulate hepatic lipogenesis is unknown, especially in perivenous areas. Here, by analyzing single-cell RNA-sequencing and in situ stable isotope tracing, we unveiled that disturbed glutamine metabolism in obese adipose tissue forced to release a neurotransmitter precursor proline to circulation, and proline was delivered by steatotic liver which had elevated expression level of proline uptake transporter solute carrier family 6 member 20 (SLC6A20). Interestingly, low dose IFN-γ produced from visceral adipose tissue natural killer cells was also reached to perivenous hepatocytes (HEPs) and mediated the metabolic conversion of proline to glutamine by inducing glutamine synthesis-related enzyme expression. Then, accumulated glutamine in perivenous HEPs activated mammalian target of rapamycin 1 (mTORC1) to trigger lipogenesis and steatosis. In vivo experiments, pharmacological inhibition of glutamine synthesis or genetic inhibition of hepatic IFN-γ signaling or mTORC1 pathway remarkably attenuated hepatic steatosis in mice. Overall, we suggested that targeting HEP-intrinsic IFN-γ signaling and glutamine metabolism is a valuable therapeutic approach in non-alcoholic hepatic steatosis.
최근 바이러스성 간염은 노벨상 수상 등 치료법 연구에 획기적인 발전이 있었으나, 대사성 간질환인 알코올성 및 비알코올성 간질환의 경우에는 아직까지 공여자 부족 현상을 겪는 간이식 외에는 치료법이 전혀 없는 상황이다. 특히, 대사성 간질환은 단순 지방간부터 간암까지 스펙트럼을 가지고 발달하는데, 초기 단계인 지방간의 경우 증상이 거의 없으므로 대부분 손상 회복이 불가능한 간경변, 간암 등 후기 단계에서 질환이 발견되어 치료가 어렵기 때문에 지방간 단계에서의 진단 표지 발굴 및 치료타겟 개발이 요구되는 상황이다. 흥미롭게도, 간세포는 간문맥에서 중심정맥으로 이어지는 고유한 혈류 구조로 인해 각 구역에 위치한 세포들이 사용 가능한 산소 및 영양분에 차이가 나게 되고, 이로 인해 서로 다른 기능을 수행한다고 알려져 있다. 특히, 최근 대사성 간질환 발달 시 알코올 대사 및 지질 생합성 역할을 수행하는 중심정맥 주변 간세포의 역할이 대두되고 있다. 또한, 최근 연구를 통해 간의 대사 및 면역 반응이 장, 지방조직, 골수, 뇌 등 다양한 조직과의 상호작용을 통해 조절되며, 세로토닌, 글루타메이트 등 신경전달물질들에 의한 간 기능 조절이 대사성 간질환 발달에 중요한 역할을 한다는 것이 보고되고 있다. 따라서 본 연구에서는 장-간 축 또는 지방조직-간 축에서 유래된 신경전달물질들에 의한 중심정맥 미세환경의 변화가 각각 알코올성 및 비알코올성 지방간의 발달에 어떻게 영향을 미치는지 연구하고자 하였다.
