LRG1, or leucine-rich α-2 glycoprotein 1, is a secreted glycoprotein. It is constitutively expressed by hepatocytes and neutrophils. LRG1 has been shown to play a role in multiple human conditions. It often exerts its functions by modulating the TGFβ signalling pathway in a context-dependent manner. LRG1 is considered an important molecule in understanding disease pathogenesis, and gene knockout (KO) mouse models have been crucial in studying its functions [1].

In various disease models, LRG1 has distinct roles. In obese mice, LRG1 deficiency alleviated diet-induced hepatosteatosis, obesity, and insulin resistance, suggesting it mediates crosstalk between adipocytes and hepatocytes in diet-induced metabolic diseases [2]. In diabetic kidney disease models, LRG1 ablation attenuated diabetes-induced glomerular angiogenesis, podocyte loss, and diabetic glomerulopathy by reducing ALK1-Smad1/5/8 activation, identifying it as a pathogenic mediator of diabetic glomerular neoangiogenesis [3]. In cerebral ischemia-reperfusion injury models, Lrg1 knockout reduced cerebral edema, infarct size, and improved neurological function by enhancing the blood-brain barrier and promoting an anti-inflammatory and tissue-repairing phenotype in microglia and macrophages [4]. In atherosclerosis models, LRG1 knockout mice showed delayed atherogenesis progression and reduced macrophage-related proinflammatory cytokines, as LRG1 promotes macrophage M1-like polarization [5].

In conclusion, LRG1 is a pleiotropic molecule that plays significant roles in multiple disease conditions, including obesity-related metabolic diseases, diabetic kidney disease, cerebral ischemia-reperfusion injury, and atherosclerosis. Gene knockout mouse models have been instrumental in uncovering these roles, highlighting LRG1 as a potential biomarker and therapeutic target in these disease areas.

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/