Orosomucoid 2 (Orm2), an acute phase protein mainly secreted by hepatocytes, plays diverse crucial roles [2,3]. In lipid metabolism, it is involved in maintaining hepatic lipid homeostasis and regulating adipose browning. In the liver, it suppresses de novo lipogenesis, while in adipose tissue, it promotes browning. Orm2 also affects the immune response and may be related to inflammatory diseases. It acts through multiple pathways such as GP130/IL23R-p38, Erk1/2-PPARγ-Cd36, and NF-κB and p38 MAPK pathways [1,2,3,4]. Genetic models, especially knockout mouse models, have been instrumental in studying its functions [3,5,6].

In mouse models, Orm2 knockout leads to various phenotypes. Orm2-/-mice on a normal diet develop spontaneous obesity and metabolic disturbances, and a high-fat diet exacerbates obesity. This is associated with gut microbial dysbiosis and intestinal inflammation, as the gut microbiota composition in Orm2-/-mice differs from wild-type mice [5]. In the context of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), Orm2 knockout mice develop spontaneous obesity under a regular diet and have exacerbated HFD-induced steatosis, steatohepatitis, and fibrosis. Mechanistically, Orm2 deletion activates the Erk1/2-PPARγ-Cd36 signaling pathway [3]. Contrarily, in diet-induced obesity models, Orm2 knockout mice show a lean phenotype under a high-fat diet, but lose the anti-obesity effect of bile acids when the diet is supplemented with cholic acid [6].

In conclusion, Orm2 is essential for maintaining lipid homeostasis, regulating adipose browning, and influencing the gut microbiota-obesity relationship. Orm2 knockout mouse models have provided insights into its role in obesity, NAFLD, NASH, and the impact of bile acids on metabolism. These findings suggest Orm2 could be a potential therapeutic target for related metabolic and inflammatory diseases [1,2,3,4,5,6].

References:

1. Zhu, Xuejuan, Wang, Xinran, Wang, Jingang, Han, Junfeng, Luan, Bing. 2024. Intermittent Fasting-Induced Orm2 Promotes Adipose Browning via the GP130/IL23R-p38 Cascade. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2407789. doi:10.1002/advs.202407789. https://pubmed.ncbi.nlm.nih.gov/39248328/

2. Zhou, Bing, Luo, Yunchen, Ji, Nana, Hu, Cheng, Lu, Yan. 2022. Orosomucoid 2 maintains hepatic lipid homeostasis through suppression of de novo lipogenesis. In Nature metabolism, 4, 1185-1201. doi:10.1038/s42255-022-00627-4. https://pubmed.ncbi.nlm.nih.gov/36050503/

3. Li, Li, Sun, Haoming, Chen, Jionghao, Han, Hua, Sun, Qingzhu. 2023. Mitigation of non-alcoholic steatohepatitis via recombinant Orosomucoid 2, an acute phase protein modulating the Erk1/2-PPARγ-Cd36 pathway. In Cell reports, 42, 112697. doi:10.1016/j.celrep.2023.112697. https://pubmed.ncbi.nlm.nih.gov/37355990/

4. Kim, Ki-Myo, Lee, Kang-Gu, Lee, Saseong, Yoo, Seung-Ah, Kim, Wan-Uk. 2024. The acute phase reactant orosomucoid-2 directly promotes rheumatoid inflammation. In Experimental & molecular medicine, 56, 890-903. doi:10.1038/s12276-024-01188-0. https://pubmed.ncbi.nlm.nih.gov/38556552/

5. Li, Li, Chen, Jionghao, Sun, Haoming, Yang, Xiaojun, Sun, Qingzhu. 2023. Orm2 Deficiency Aggravates High-Fat Diet-Induced Obesity through Gut Microbial Dysbiosis and Intestinal Inflammation. In Molecular nutrition & food research, 68, e2300236. doi:10.1002/mnfr.202300236. https://pubmed.ncbi.nlm.nih.gov/37853937/

6. Lee, Sung Ho, Suh, Ji Ho, Heo, Mi Jeong, Moore, David D, Kim, Kang Ho. . The Hepatokine Orosomucoid 2 Mediates Beneficial Metabolic Effects of Bile Acids. In Diabetes, 73, 701-712. doi:10.2337/db23-0520. https://pubmed.ncbi.nlm.nih.gov/38320268/