Disease relevance of Angptl4

• In addition, MHC-Angptl4 mice also exhibit hypertriglyceridemia after 6 h of fasting [1].
• We use echocardiography to show that MHC-Angptl4 mice develop left-ventricular dysfunction [1].
• Thus, GF animals are protected from diet-induced obesity by two complementary but independent mechanisms that result in increased fatty acid metabolism: (i) elevated levels of Fiaf, which induces Pgc-1alpha; and (ii) increased AMPK activity [2].
• Our data indicate that disturbances in FIAF signaling might be involved in dyslipidemia [3].
• We show that neonatal hypoxia/ischaemia rapidly increased fiaf mRNA in the injured cortex and hippocampus at 2 and 7 days after hypoxia/ischaemia [4].

High impact information on Angptl4

• Moreover, GF knockout mice lacking fasting-induced adipose factor (Fiaf), a circulating lipoprotein lipase inhibitor whose expression is normally selectively suppressed in the gut epithelium by the microbiota, are not protected from diet-induced obesity [2].
• Although GF Fiaf-/- animals exhibit similar levels of phosphorylated AMPK as their wild-type littermates in liver and gastrocnemius muscle, they have reduced expression of genes encoding the peroxisomal proliferator-activated receptor coactivator (Pgc-1alpha) and enzymes involved in fatty acid oxidation [2].
• Using knockout mice, we found that fasting-induced adipose factor (Fiaf) is required for functional partitioning of postnatal intestinal lymphatic and blood vessels [5].
• Postnatal lymphatic partitioning from the blood vasculature in the small intestine requires fasting-induced adipose factor [5].
• We identified Prox1, a critical regulator of lymphangiogenesis, as a downstream target for Fiaf signaling in the intestinal lymphatic endothelium [5].

Biological context of Angptl4

• Transactivation, chromatin immunoprecipitation, and gel shift experiments identified a functional PPAR response element within intron 3 of the FIAF gene [6].
• We show that MHC-Angptl4 mice exhibit cardiac-restricted expression of the transgene and inhibition of cardiac lipoprotein lipase (LPL) activity [1].
• Our results show that Angptl3 and Angptl4 function to regulate circulating triglyceride levels during different nutritional states and therefore play a role in lipid metabolism during feeding/fasting through differential inhibition of LPL [7].
• We now show that adenoviral overexpression of Angptl4 potently increases plasma TG levels by a mechanism independent of food intake or hepatic VLDL secretion [8].
• Our previous studies of gene expression profiling during collagen-induced arthritis (CIA) indicated that the putative angiogenic factor Angptl4 was one of the most highly expressed mRNAs early in disease [9].

Anatomical context of Angptl4

• Differentiation of mouse 3T3-L1 adipocytes was associated with the production of truncated FIAF, whereas in human white adipose tissue and SGBS adipocytes, only native FIAF could be detected [6].
• At the protein level, in human and mouse blood plasma, FIAF was found to be present both as the native protein and in a truncated form [6].
• To further characterize FIAF, we studied regulation of FIAF mRNA and protein in liver and adipose cell lines as well as in human and mouse plasma [6].
• In addition, the functional effects of mouse Angptl4 on endothelial cells were assessed [9].
• In situ hybridization localized Angptl4 mRNA to stromal fibroblast-like cells within the inflamed synovium [9].

Associations of Angptl4 with chemical compounds

• Treatment with fenofibrate, a potent PPARalpha agonist, markedly increased plasma levels of truncated FIAF, but not native FIAF, in humans [6].
• Comparison of the metabolic profiles of isolated working hearts demonstrates that cardiac impairment in MHC-Angptl4 mice is positively associated with decreased triglyceride (TG) utilization [1].
• We determined that cysteine residues at positions 76 and 80 of Angptl4, conserved among mouse, rat, and human, are required to form higher order structures [8].
• Angptl3 and Angptl4 have been shown to regulate fat, lipid or glucose metabolic homeostasis [10].
• The effects of FIAF overexpression were amplified by a high fat diet, resulting in markedly elevated plasma and liver triglycerides, plasma free fatty acids, and plasma glycerol levels, and impaired glucose tolerance in FIAF transgenic mice fed a high fat diet [3].

Other interactions of Angptl4

• Increased expression of the adipokine genes resistin and fasting-induced adipose factor in hypoxic/ischaemic mouse brain [4].

Analytical, diagnostic and therapeutic context of Angptl4

• Levels of both truncated and native FIAF showed marked interindividual variation but were not associated with body mass index and were not influenced by prolonged semistarvation [6].
• Using degenerate PCR we isolated a cDNA encoding a novel 406- and 410-amino acid protein from human and mouse embryonic cDNAs and have designated it 'hepatic fibrinogen/angiopoietin-related protein' (HFARP) [11].
• This organ-specific lymphovascular abnormality can be rescued by allowing embryonic Fiaf-/- intestinal isografts to develop in Fiaf+/+ recipients [5].

References