Background & Aims: Imbalance in lipid metabolism is the main cause of nonalcoholic fatty liver disease (NAFLD). While the pathogenesis of lipid accumulation mediated by extrahepatic regulators has been extensively studied, the intrahepatic regulators modulating lipid homeostasis remain unclear. Previous studies have shown that systemic administration of interleukin-22 (IL-22) protects against NAFLD; however, the role of IL-22/IL22RA1 signaling in modulating hepatic lipid metabolism remains uncertain. Approach & Results: This study shows hepatic IL22RA1 is vital in hepatic lipid regulation. IL22RA1 is downregulated in palmitic acid-treated mouse primary hepatocytes, as well as in the livers of NAFLD model mice and patients. Hepatocyte-specific Il22ra1 knockout (HKO) mice display diet-induced hepatic steatosis, insulin resistance, impaired glucose tolerance, increased inflammation, and fibrosis compared with flox/flox mice. This is attributed to increased lipogenesis mediated by the accumulation of hepatic oxysterols, particularly, 3 beta-hydroxy-5-cholestenoic acid (3β HCA). Mechanistically, hepatic IL22RA1 deficiency facilitates 3β HCA deposition via the activating transcription factor 3 (ATF3)/oxysterol 7 alpha-hydroxylase (CYP7B1) axis. Notably, 3β HCA facilitates lipogenesis in MPHs and human liver organoids (HLOs) by activating LXR-alpha signaling, but IL-22 treatment attenuates this effect. Additionally, restoring CYP7B1 or silencing hepatic ATF3 reduces both hepatic 3β HCA and lipid contents in HKO mice. Conclusions: These findings indicate that IL22RA1 plays a crucial role in maintaining hepatic lipid homeostasis in an ATF3/CYP7B1-dependent manner, and establish a link between 3β HCA and hepatic lipid homeostasis.

中文翻译：

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肝脏 IL22RA1 缺乏通过调节肝脏中的氧甾醇促进肝脏脂肪变性


背景与目的：脂质代谢失衡是非酒精性脂肪肝（NAFLD）的主要原因。虽然肝外调节因子介导的脂质积累的发病机制已被广泛研究，但调节脂质稳态的肝内调节因子仍不清楚。先前的研究表明，全身注射白细胞介素 22 (IL-22) 可预防 NAFLD；然而，IL-22/IL22RA1 信号在调节肝脂质代谢中的作用仍不确定。方法和结果：本研究表明肝脏 IL22RA1 在肝脏脂质调节中至关重要。 IL22RA1 在棕榈酸处理的小鼠原代肝细胞以及 NAFLD 模型小鼠和患者的肝脏中下调。肝细胞特异性伊尔22ra1与 flox/flox 小鼠相比，敲除 (HKO) 小鼠表现出饮食诱导的肝脂肪变性、胰岛素抵抗、糖耐量受损、炎症增加和纤维化。这是由于肝氧甾醇，特别是 3β-羟基-5-胆烯酸 (3β HCA) 的积累介导的脂肪生成增加。从机制上讲，肝脏 IL22RA1 缺陷通过激活转录因子 3 (ATF3)/氧化甾醇 7 α-羟化酶 (CYP7B1) 轴促进 3β HCA 沉积。值得注意的是，3β HCA 通过激活 LXR-α 信号传导促进 MPH 和人肝类器官 (HLO) 中的脂肪生成，但 IL-22 治疗减弱了这种作用。此外，恢复 CYP7B1 或沉默肝脏 ATF3 会降低 HKO 小鼠肝脏 3β HCA 和脂质含量。结论：这些研究结果表明，IL22RA1 以 ATF3/CYP7B1 依赖性方式在维持肝脂质稳态中发挥着至关重要的作用，并在 3β HCA 和肝脂质稳态之间建立了联系。