Montgomery Magdalene K, Bayliss Jacqueline, Nie Shuai, De Nardo William, Keenan Stacey N, Miotto Paula M, Karimkhanloo Hamzeh, Huang Cheng, Schittenhelm Ralf B, Don Anthony S, Ryan Andrew, Williamson Nicholas A, Ooi Geraldine J, Brown Wendy A, Burton Paul R, Parker Benjamin L, Watt Matthew J
Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia.
Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne, Melbourne, VIC, 3010, Australia.
Nat Commun. 2022 Mar 10;13(1):1259. doi: 10.1038/s41467-022-28889-2.
Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, yet the pathophysiological mechanisms underpinning this bidirectional relationship remain unresolved. Using proteomic approaches, we interrogate hepatocyte protein secretion in two models of murine NASH to understand how liver-derived factors modulate lipid metabolism and insulin sensitivity in peripheral tissues. We reveal striking hepatokine remodelling that is associated with insulin resistance and maladaptive lipid metabolism, and identify arylsulfatase A (ARSA) as a hepatokine that is upregulated in NASH and type 2 diabetes. Mechanistically, hepatic ARSA reduces sulfatide content and increases lysophosphatidylcholine (LPC) accumulation within lipid rafts and suppresses LPC secretion from the liver, thereby lowering circulating LPC and lysophosphatidic acid (LPA) levels. Reduced LPA is linked to improvements in skeletal muscle insulin sensitivity and systemic glycemic control. Hepatic silencing of Arsa or inactivation of ARSA's enzymatic activity reverses these effects. Together, this study provides a unique resource describing global changes in hepatokine secretion in NASH, and identifies ARSA as a regulator of liver to muscle communication and as a potential therapeutic target for type 2 diabetes.
非酒精性脂肪性肝炎（NASH）与2型糖尿病密切相关，然而这种双向关系背后的病理生理机制仍未明确。我们运用蛋白质组学方法，在两种小鼠NASH模型中研究肝细胞蛋白质分泌情况，以了解肝脏来源的因子如何调节外周组织中的脂质代谢和胰岛素敏感性。我们发现了与胰岛素抵抗和适应性脂质代谢不良相关的显著肝细胞因子重塑现象，并确定芳基硫酸酯酶A（ARSA）是一种在NASH和2型糖尿病中上调的肝细胞因子。从机制上讲，肝脏中的ARSA会降低硫苷脂含量，增加脂筏内溶血磷脂酰胆碱（LPC）的积累，并抑制肝脏中LPC的分泌，从而降低循环中的LPC和溶血磷脂酸（LPA）水平。LPA的减少与骨骼肌胰岛素敏感性的改善和全身血糖控制有关。肝脏中Arsa基因的沉默或ARSA酶活性的失活会逆转这些作用。总之，本研究提供了一份独特的资源，描述了NASH中肝细胞因子分泌的整体变化，并确定ARSA是肝脏与肌肉间通讯的调节因子以及2型糖尿病的潜在治疗靶点。
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