美国耶鲁大学Richard A. Flavell研究小组发现，人源化小鼠肝脏揭示内皮对基本肝脏代谢功能的控制。该项研究成果于2023年8月9日在线发表在《细胞》杂志上。

研究人员发现人类肝细胞的关键代谢功能受其微环境中的非实质性细胞（NPC）控制。研究人员培育了携带由人类肝细胞和非实质性细胞（包括人类免疫细胞、内皮细胞和星状细胞）组成的人类肝组织小鼠。人源化肝脏再现了人类肝脏结构，执行重要的人类特异性新陈代谢/体内平衡过程，并模拟人类病症，包括肝纤维化和非酒精性脂肪肝（NAFLD）。

利用物种错配和脂质组学，研究人员证明了人类NPC以旁分泌方式控制人类肝细胞的代谢功能。从机理上讲，研究人员发现了一种物种特异性相互作用，即窦状内皮细胞分泌的WNT2通过受体FZD5控制肝细胞的胆固醇摄取和胆汁酸结合。这些结果揭示了肝脏代谢的重要微环境调控及其人类特异性。

据悉，肝细胞是人体的主要代谢枢纽，其功能具有人类特异性，在人类疾病中会发生改变，目前认为肝细胞的功能是通过内分泌和细胞自主机制调节的。

附：英文原文

Title: Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions

Author: Eleanna Kaffe, Manolis Roulis, Jun Zhao, Rihao Qu, Esen Sefik, Haris Mirza, Jing Zhou, Yunjiang Zheng, Georgia Charkoftaki, Vasilis Vasiliou, Daniel F. Vatner, Wajahat Z. Mehal, Yuval Kluger, Richard A. Flavell

Issue&Volume: 2023-08-09

Abstract: Hepatocytes, the major metabolic hub of the body, execute functions that are human-specific,altered in human disease, and currently thought to be regulated through endocrineand cell-autonomous mechanisms. Here, we show that key metabolic functions of humanhepatocytes are controlled by non-parenchymal cells (NPCs) in their microenvironment.We developed mice bearing human hepatic tissue composed of human hepatocytes and NPCs,including human immune, endothelial, and stellate cells. Humanized livers reproducehuman liver architecture, perform vital human-specific metabolic/homeostatic processes,and model human pathologies, including fibrosis and non-alcoholic fatty liver disease(NAFLD). Leveraging species mismatch and lipidomics, we demonstrate that human NPCscontrol metabolic functions of human hepatocytes in a paracrine manner. Mechanistically,we uncover a species-specific interaction whereby WNT2 secreted by sinusoidal endothelialcells controls cholesterol uptake and bile acid conjugation in hepatocytes throughreceptor FZD5. These results reveal the essential microenvironmental regulation ofhepatic metabolism and its human-specific aspects.

DOI: 10.1016/j.cell.2023.07.017

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00795-X