LRG1, or leucine-rich α-2 glycoprotein 1, is a secreted glycoprotein. Although its normal physiological function remains somewhat unclear, it has been implicated in multiple biological processes mainly through modulating the TGFβ signalling pathway. It is constitutively expressed by hepatocytes and neutrophils, yet Lrg1 -/- mice show no overt phenotypic abnormality, initially suggesting redundancy in development and homeostasis [1].

In disease contexts, LRG1 has been widely studied. In obesity, LRG1 is identified as an adipokine. LRG1 deficiency in mice alleviated diet-induced hepatosteatosis, obesity, and insulin resistance, indicating its role in mediating the crosstalk between adipocytes and hepatocytes [2]. In diabetic kidney disease, LRG1 ablation in mice attenuated diabetes-induced glomerular angiogenesis, podocyte loss, and diabetic glomerulopathy, highlighting its role in promoting disease progression [3]. In cerebral ischemia-reperfusion injury, Lrg1 knockout in mice reduced cerebral edema, infarct size, and improved neurological function, suggesting Lrg1 mediates pathological processes through altering various cell functional states [4]. In atherosclerosis, LRG1 knockout mice showed delayed atherogenesis progression and reduced macrophage-related proinflammatory cytokines, demonstrating its role in promoting the disease by inducing macrophage M1-like polarization [5].

In conclusion, LRG1, through its modulation of the TGFβ signalling pathway, plays a significant role in various disease conditions such as obesity-related metabolic diseases, diabetic kidney disease, cerebral ischemia-reperfusion injury, and atherosclerosis. The use of Lrg1 knockout mouse models has been instrumental in uncovering its pathogenic roles in these diseases, suggesting LRG1 could be a potential therapeutic target for these conditions.

References:

1. Camilli, Carlotta, Hoeh, Alexandra E, De Rossi, Giulia, Moss, Stephen E, Greenwood, John. 2022. LRG1: an emerging player in disease pathogenesis. In Journal of biomedical science, 29, 6. doi:10.1186/s12929-022-00790-6. https://pubmed.ncbi.nlm.nih.gov/35062948/

2. He, Sijia, Ryu, Jiyoon, Liu, Juanhong, Bai, Juli, Dong, Lily Q. . LRG1 is an adipokine that mediates obesity-induced hepatosteatosis and insulin resistance. In The Journal of clinical investigation, 131, . doi:10.1172/JCI148545. https://pubmed.ncbi.nlm.nih.gov/34730111/

3. Hong, Quan, Zhang, Lu, Fu, Jia, He, John C, Lee, Kyung. 2019. LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β-Induced Angiogenesis. In Journal of the American Society of Nephrology : JASN, 30, 546-562. doi:10.1681/ASN.2018060599. https://pubmed.ncbi.nlm.nih.gov/30858225/

4. Ruan, Zhaohui, Cao, Guosheng, Qian, Yisong, Wu, Yaoqi, Lv, Yanni. 2023. Single-cell RNA sequencing unveils Lrg1's role in cerebral ischemia‒reperfusion injury by modulating various cells. In Journal of neuroinflammation, 20, 285. doi:10.1186/s12974-023-02941-4. https://pubmed.ncbi.nlm.nih.gov/38037097/

5. Wang, Juan, Wang, Jing, Zhong, Jiuchang, Zhang, Sitao, Wang, Xiaodong. 2024. LRG1 promotes atherosclerosis by inducing macrophage M1-like polarization. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2405845121. doi:10.1073/pnas.2405845121. https://pubmed.ncbi.nlm.nih.gov/39178231/