Angptl4, also known as Angiopoietin-like 4, is a secreted glycoprotein with a key role in lipid metabolism. It is predominantly expressed in adipose tissue and liver. Angptl4 inhibits the activity of lipoprotein lipase (LPL), a rate-limiting enzyme for intravascular processing of triglyceride-rich lipoproteins, thereby promoting an increase in circulating triglyceride levels [1,2,6]. It is also involved in multiple biological activities such as angiogenesis, glucose metabolism, and tumor growth [5].

In atherosclerotic Apoe-/-mice, injection of Angptl4 protein reduced atherosclerotic plaque size, vascular inflammation, and stabilized atherosclerotic plaques by modulating the phenotypic transition of vascular smooth muscle cells through KLF4 downregulation [3]. In diabetic kidney disease, podocyte-and tubule-specific Angptl4 mutant mice showed a reduction in fibrosis-related phenotypes compared to control mice, indicating that Angptl4 is a key fibrogenic molecule in diabetes [4].

In conclusion, Angptl4 is a multifunctional protein with a crucial role in lipid metabolism, and its functions extend to various disease conditions such as atherosclerosis and diabetic kidney disease. The use of gene-knockout (KO) or conditional-knockout (CKO) mouse models has been instrumental in revealing these functions, providing insights into potential therapeutic strategies for these diseases.

References:

1. Fernández-Hernando, Carlos, Suárez, Yajaira. . ANGPTL4: a multifunctional protein involved in metabolism and vascular homeostasis. In Current opinion in hematology, 27, 206-213. doi:10.1097/MOH.0000000000000580. https://pubmed.ncbi.nlm.nih.gov/32205586/

2. 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/

3. Cho, Dong Im, Ahn, Min Joo, Cho, Hyang Hee, Kim, Yong Sook, Ahn, Youngkeun. 2023. ANGPTL4 stabilizes atherosclerotic plaques and modulates the phenotypic transition of vascular smooth muscle cells through KLF4 downregulation. In Experimental & molecular medicine, 55, 426-442. doi:10.1038/s12276-023-00937-x. https://pubmed.ncbi.nlm.nih.gov/36782020/

4. Srivastava, Swayam Prakash, Zhou, Han, Shenoi, Rachel, Shulman, Gerald I, Goodwin, Julie E. 2024. Renal Angptl4 is a key fibrogenic molecule in progressive diabetic kidney disease. In Science advances, 10, eadn6068. doi:10.1126/sciadv.adn6068. https://pubmed.ncbi.nlm.nih.gov/39630889/

5. Xu, Zhilong, Jiang, Gening. . ANGPTL4-A protein involved in glucose metabolism, lipid metabolism, and tumor development. In The journal of gene medicine, 26, e3740. doi:10.1002/jgm.3740. https://pubmed.ncbi.nlm.nih.gov/39467822/

6. Ploug, Michael. . ANGPTL4: a new mode in the regulation of intravascular lipolysis. In Current opinion in lipidology, 33, 112-119. doi:10.1097/MOL.0000000000000800. https://pubmed.ncbi.nlm.nih.gov/34860701/