ANGPTL8, also known as betatrophin, is an important cytokine and a novel but atypical member of the ANGPTL family. It plays vital roles in modulating serum glucose and lipid metabolism by regulating lipoprotein lipase (LPL) activity [2,3,4,5,6,7,8]. It has been associated with inflammation and metabolic syndrome consequences. Genetic models like knockout mice are valuable for studying its functions [1].

ANGPTL8 knockout (KO) mouse studies demonstrated that ANGPTL8 deficiency suppresses high-fat diet (HFD)-stimulated inflammatory activity, hepatic steatosis and liver fibrosis. Restoration of liver ANGPTL8 expression in KO mice accelerated HFD-induced liver fibrosis. Liver-derived ANGPTL8, as a pro-inflammatory factor, activates hepatic stellate cells (HSCs) by interacting with the LILRB2 receptor to induce ERK signaling, promoting liver fibrosis [1]. In ApoE-/-mice, ANGPTL8 knockout significantly reduced angiotensin II (AngII)-induced abdominal aortic aneurysm (AAA) formation, elastin breaks, aortic inflammatory cytokines, matrix metalloproteinase expression, and smooth muscle cell apoptosis [9].

In conclusion, ANGPTL8 is a key regulator in glucose and lipid metabolism, and inflammation. KO mouse models have revealed its roles in liver fibrosis and AAA, suggesting it could be a potential therapeutic target for non-alcoholic fatty liver disease-associated liver fibrosis and AAA [1,9].

References:

1. Zhang, Zongli, Yuan, Yue, Hu, Lin, Ruan, Xuzhi, Guo, Xingrong. 2022. ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways. In Journal of advanced research, 47, 41-56. doi:10.1016/j.jare.2022.08.006. https://pubmed.ncbi.nlm.nih.gov/36031141/

2. Su, Xin, Cheng, Ye, Wang, Bin. 2021. ANGPTL8 in cardio-metabolic diseases. In Clinica chimica acta; international journal of clinical chemistry, 519, 260-266. doi:10.1016/j.cca.2021.05.017. https://pubmed.ncbi.nlm.nih.gov/34023284/

3. Guo, Chang, Wang, Chenxi, Deng, Xia, Yang, Ling, Yuan, Guoyue. 2021. ANGPTL8 in metabolic homeostasis: more friend than foe? In Open biology, 11, 210106. doi:10.1098/rsob.210106. https://pubmed.ncbi.nlm.nih.gov/34582711/

4. Sylvers-Davie, Kelli L, Davies, Brandon S J. 2021. Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8. In American journal of physiology. Endocrinology and metabolism, 321, E493-E508. doi:10.1152/ajpendo.00195.2021. https://pubmed.ncbi.nlm.nih.gov/34338039/

5. Luo, Mengdie, Peng, Daoquan. 2018. ANGPTL8: An Important Regulator in Metabolic Disorders. In Frontiers in endocrinology, 9, 169. doi:10.3389/fendo.2018.00169. https://pubmed.ncbi.nlm.nih.gov/29719529/

6. Navaeian, Maryam, Asadian, Samieh, Ahmadpour Yazdi, Hossein, Gheibi, Nematollah. 2021. ANGPTL8 roles in proliferation, metabolic diseases, hypothyroidism, polycystic ovary syndrome, and signaling pathways. In Molecular biology reports, 48, 3719-3731. doi:10.1007/s11033-021-06270-8. https://pubmed.ncbi.nlm.nih.gov/33864588/

7. Abu-Farha, Mohamed, Abubaker, Jehad, Tuomilehto, Jaakko. 2017. ANGPTL8 (betatrophin) role in diabetes and metabolic diseases. In Diabetes/metabolism research and reviews, 33, . doi:10.1002/dmrr.2919. https://pubmed.ncbi.nlm.nih.gov/28722798/

8. Su, Xin, Zhang, Guoming, Cheng, Ye, Wang, Bin. 2021. New insights into ANGPTL8 in modulating the development of cardio-metabolic disorder diseases. In Molecular biology reports, 48, 3761-3771. doi:10.1007/s11033-021-06335-8. https://pubmed.ncbi.nlm.nih.gov/33864591/

9. Yu, Huahui, Jiao, Xiaolu, Yang, Yunyun, Zhang, Xiaoping, Qin, Yanwen. . ANGPTL8 deletion attenuates abdominal aortic aneurysm formation in ApoE-/- mice. In Clinical science (London, England : 1979), 137, 979-993. doi:10.1042/CS20230031. https://pubmed.ncbi.nlm.nih.gov/37294581/