ANGPTL4, short for Angiopoietin-like 4, is a secreted glycoprotein with a key role in lipid metabolism [1]. It mainly functions by inhibiting the activity of lipoprotein lipase (LPL), which hydrolyzes fatty acids from triglyceride-rich lipoproteins. This inhibition leads to an increase in circulating triglyceride levels. ANGPTL4 is predominantly expressed in adipose tissue and liver and is involved in multiple biological processes including angiogenesis, glucose metabolism, and vascular homeostasis [1,4]. Genetic models, such as knockout (KO) or conditional knockout (CKO) mouse models, are valuable tools to study its functions.

In KO mouse models, diabetes-induced fibrogenic phenotype was accelerated in control mice but not in ANGPTL4 mutant mice. This indicates that ANGPTL4 is a crucial fibrogenic molecule in diabetes. The protective effect in mutant mice was associated with reduced activation of certain pathways, decreased pro-inflammatory cytokines, lessened epithelial-to-mesenchymal transition, and increased fatty acid oxidation [3]. In atherosclerotic Apoe -/- mice, injection of ANGPTL4 protein reduced atherosclerotic plaque size, vascular inflammation, and modulated the phenotypic transition of vascular smooth muscle cells, leading to more stable plaques [2].

In conclusion, ANGPTL4 is a multifunctional protein with essential roles in lipid metabolism, glucose metabolism, and maintaining vascular homeostasis. Model-based research, especially using KO/CKO mouse models, has revealed its significance in diseases like diabetes-related kidney disease and atherosclerosis, providing potential therapeutic targets for these conditions.

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. 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/

3. 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/

4. 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/