ANGPTL4

Angiopoietin-like 4 is a is_associated_with::protein that in human is encoded by the ANGPTL4 is_associated_with::gene. Alternatively spliced transcript variants encoding different isoforms have been described. This gene was previously referred to as ANGPTL2, HFARP, PGAR, or FIAF but has been renamed ANGPTL4.

Structure
This gene is a member of the is_associated_with::angiopoietin-like gene family and encodes a is_associated_with::glycosylated, secreted protein with a is_associated_with::coiled-coil is_associated_with::N-terminal domain and a is_associated_with::fibrinogen-like is_associated_with::C-terminal domain.

Expression
In mice, highest mRNA expression levels of ANGPTL4 are found in white and brown adipose tissue, followed by liver, kidney, muscle and intestine. Human ANGPTL4 is most highly expressed in liver.

Function
This gene is induced under hypoxic (low oxygen) condition in various cell types and is the target of is_associated_with::Peroxisome proliferator-activated receptors. The encoded protein is a serum hormone directly involved in regulating lipid metabolism. The native full length ANGPTL4 can form higher order structures via intermolecular disulfide bonds. The N-terminal region of ANGPTL4 (nANGPTL4) is responsible for its assembly. The full length ANGPTL4 undergoes proteolytic cleavage at the linker region, releasing nANGPTL4 and the monomeric C-terminal portion of ANGPTL4 (cANGPTL4). The nANGPTL4 and cANGPTL4 have different biological functions. Monoclonal antibodies targeting the nANGPTL4 and cANGPTL4 have been developed to distinguish their functions.

Clinical significance
ANGPTL4 plays an important role in numerous cancers and it is implicated in the metastatic process by modulating vascular permeability, cancer cell motility and invasiveness. ANGPTL4 contributes to tumor growth and protects cells from is_associated_with::anoikis, a form of is_associated_with::programmed cell death induced when contact-dependent cells detach from the surrounding tissue matrix. ANGPTL4 secreted from tumors can bind to is_associated_with::integrins, activating downstream signaling and leading to the production of is_associated_with::superoxide to promote is_associated_with::tumorigenesis. ANGPTL4 disrupts endothelial is_associated_with::cell junctions by directly interacting with integrin, is_associated_with::VE-cadherin and claudin-5 in a sequential manner to facilitate is_associated_with::metastasis. ANGPTL4 functions as a is_associated_with::matricellular protein to facilitate skin wound healing. ANGPTL4-deficient mice exhibit delayed wound reepithelialization with impaired is_associated_with::keratinocyte migration, angiogenesis and altered inflammatory response. ANGPTL4 induces is_associated_with::nitric oxide production through an integrin/JAK/STAT3-mediated upregulation of is_associated_with::iNOS expression in wound epithelia, and enhances angiogenesis to accelerate wound healing in diabetic mice.

ANGPTL4 has been established as a potent inhibitor of serum is_associated_with::triglyceride (TG) clearance, causing elevation of serum TG levels via inhibition of the enzyme is_associated_with::lipoprotein lipase (LPL). Biochemical studies indicate that ANGPTL4 disables LPL partly by dissociating the catalytically active LPL dimer into inactive LPL monomers. However, evidence also suggests that ANGPTL4 functions as a conventional, non-competitive inhibitor that binds to LPL to prevent the hydrolysis of substrate as part of reversible mechanism. As a consequence, ANGPTL4 knockout mice have reduced serum triglyceride levels, whereas the opposite is true for mice over-expressing ANGPTL4. ANGPTL4 suppresses foam cell formation to reduce is_associated_with::atherosclerosis development. The reduction in LPL activity in is_associated_with::adipose tissue during fasting is likely caused by increased local production of ANGPTL4. In other tissues such as heart, production of ANGPTL4 is stimulated by is_associated_with::fatty acids and may serve to protect cells against excess fat uptake. ANGPTL4 is more highly induced in nonexercising muscle than in exercising human muscle during acute exercise. ANGPTL4 in nonexercising muscle presumably leads to reduced local uptake of plasma triglyceride-derived fatty acids and their sparing for use by exercising muscle. The induction of ANGPTL4 in exercising muscle likely is counteracted via is_associated_with::AMP-activated protein kinase (AMPK)-mediated down-regulation, promoting the use of plasma triglycerides as fuel for active muscles.

High-throughput RNA sequencing of lung tissue samples from the 1918 and 2009 is_associated_with::influenza pandemic revealed that ANGPTL4 was one of the most significantly upregulated gene. Murine influenza infection of the lungs stimulated the expression of ANGPTL4 via a STAT3-mediated mechanism. ANGPTL4 enhanced pulmonary tissue leakiness and exacerbated inflammation-induced lung damage. Influenza-infected ANGPTL4-knockout mice displayed diminished lung damage and recovered faster from the infection compared to wild-type mice. The treatment of infected mice with neutralizing anti-ANGPTL4 antibodies significantly accelerated pulmonary recovery and improved lung tissue integrity.