Study for the zone-dependent regulatory mechanisms in hepatic steatosis through inter-organ crosstalk

Abstract

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.