Angptl 4 deficiency improves lipid metabolism, suppresses foam cell formation and protects against atherosclerosis

Adachi, Hironori; Fujiwara, Yukio; Kondo, Tatsuya; Nishikawa, Takeshi; Ogawa, Rei; Matsumura, Takeshi; Ishii, Norio; Nagai, Ryoji; Miyata, Keishi; Tabata, Mitsuhisa; Motoshima, Hiroyuki; Furukawa, Noboru; Tsuruzoe, Kaku; Kawashima, Junji; Takeya, Motohiro; Yamashita, Shizuya; Koh, Gou Young; Nagy, András; Suda, Toshio; Oike, Yuichi; Araki, Eiichi

doi:10.1016/j.bbrc.2008.12.018

Cited by 76 publications

(57 citation statements)

References 22 publications

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“…Antibodies against nANGPTL4 could potentially lower the levels of triglycerides and cholesterol in patients with heart disease (http:// www.lexpharma.com/news/2007-07-02-160145.html). The targeted silencing of ANGPTL4 offers another potential therapeutic strategy in the treatment of atherosclerosis, dyslipidemia, and diabetic wounds (8,14,51,52). These reports emphasize the clinical relevance of ANGPTL4 as an attractive therapeutic candidate.…”

Section: Clinical Relevance Of Angptl4mentioning

confidence: 91%

Emerging Roles of Angiopoietin-like 4 in Human Cancer

Tan

Teo

Sng

et al. 2012

Molecular Cancer Research

155

166

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Angiopoietin-like 4 (ANGPTL4) is best known for its role as an adipokine involved in the regulation of lipid and glucose metabolism. The characterization of ANGPTL4 as an adipokine is largely due to our limited understanding of the interaction partners of ANGPTL4 and how ANGPTL4 initiates intracellular signaling. Recent findings have revealed a critical role for ANGPTL4 in cancer growth and progression, anoikis resistance, altered redox regulation, angiogenesis, and metastasis. Emerging evidence suggests that ANGPTL4 function may be drastically altered depending on the proteolytic processing and posttranslational modifications of ANGPTL4, which may clarify several conflicting roles of ANGPTL4 in different cancers. Although the N-terminal coiled-coil region of ANGPTL4 has been largely responsible for the endocrine regulatory role in lipid metabolism, insulin sensitivity, and glucose homeostasis, it has now emerged that the COOH-terminal fibrinogen-like domain of ANGPTL4 may be a key regulator in the multifaceted signaling during cancer development. New insights into the mechanistic action of this functional domain have opened a new chapter into the possible clinical application of ANGPTL4 as a promising candidate for clinical intervention in the fight against cancer. This review summarizes our current understanding of ANGPTL4 in cancer and highlights areas that warrant further investigation. A better understanding of the underlying cellular and molecular mechanisms of ANGPTL4 will reveal novel insights into other aspects of tumorigenesis and the potential therapeutic value of ANGPTL4. Mol Cancer Res; 10(6); 677-88. Ó2012 AACR.

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Section: Clinical Relevance Of Angptl4mentioning

confidence: 91%

Emerging Roles of Angiopoietin-like 4 in Human Cancer

Tan

Teo

Sng

et al. 2012

Molecular Cancer Research

155

166

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“…Mainly produced in hepatocytes in humans and adipocytes in mice, ANGPTL4 exerts its biological effects by means of autocrine/ paracrine and endocrine processes. ANGPTL4 has been implicated in a variety of diseases, including cardiovascular disease (1,2), cancer metastasis (3), obesity (4), diabetes (5), wound repair (6, 7), inflammation (8), and arthritis (9).…”

mentioning

confidence: 99%

Proteolytic Processing of Angiopoietin-like Protein 4 by Proprotein Convertases Modulates Its Inhibitory Effects on Lipoprotein Lipase Activity

Xia

Shi

Basu

et al. 2011

Journal of Biological Chemistry

130

101

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Angiopoietin-like protein 4 (ANGPTL4) has been associated with a variety of diseases. It is known as an endogenous inhibitor of lipoprotein lipase (LPL), and it modulates lipid deposition and energy homeostasis. ANGPTL4 is cleaved by unidentified protease(s), and the biological importance of this cleavage event is not fully understood with respect to its inhibitory effect on LPL activity. Here, we show that ANGPTL4 appears on the cell surface as the full-length form, where it can be released by heparin treatment in culture and in vivo. ANGPTL4 protein is then proteolytically cleaved into several forms by proprotein convertases (PCs). Several PCs, including furin, PC5/6, paired basic amino acid-cleaving enzyme 4, and PC7, are able to cleave human ANGPTL4 at a consensus site. PC-specific inhibitors block the processing of ANGPTL4. Blockage of ANGPTL4 cleavage reduces its inhibitory effects on LPL activity and decreases its ability to raise plasma triglyceride levels. In summary, the cleavage of ANGPTL4 by these PCs modulates its inhibitory effect on LPL activity.Angiopoietin-like protein 4 (ANGPTL4) is also known as hepatic fibrinogen/angiopoietin-related protein, fasting-induced adipose factor, peroxisome proliferator-activated receptors, and ␥-angiopoietin-related protein. It is one of the seven members of the ANGPTL family (ANGPTL1-7). Mainly produced in hepatocytes in humans and adipocytes in mice, ANGPTL4 exerts its biological effects by means of autocrine/ paracrine and endocrine processes. ANGPTL4 has been implicated in a variety of diseases, including cardiovascular disease (1, 2), cancer metastasis (3), obesity (4), diabetes (5), wound repair (6, 7), inflammation (8), and arthritis (9).ANGPTL4 is a fusion protein consisting of an N-terminal coiled-coil domain and a C-terminal fibrinogen-like domain.These two domains have been shown to have distinct biological functions (10). The N-terminal domain is responsible for the inhibitory effects on LPL, 4 converting the active form of LPL into an inactive form (11), and the C terminus mediates its antiangiogenic functions (12). Interestingly, these two domains are separated by a short linker that can be cleaved after secretion. The cleavage phenomenon has been shown to occur in humans as well as in rodents (13,14). Cleavage of ANGPTL4 appears to be tissue-dependent in humans; liver secretes cleaved ANGPTL4, whereas adipose tissue secretes the fulllength form (14).The physiological relevance of the proteolytic processing of ANGPTL4 is largely unknown. In a human study, treatment with fenofibrate, a potent peroxisome proliferator-activated receptor-␣ agonist, markedly increased plasma levels of cleaved ANGPTL4. On this basis, it was proposed that the cleaved form of ANGPTL4 may have specific functions (14). There is evidence that the antiangiogenic activity of ANGPTL4 is regulated by an interaction of its coiled-coil domain with heparan sulfate proteoglygans (HSPGs) (18). This may be due to an ability of the N-terminal domain to facilitate the interaction between t...

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“…A previous study found that upregulation of ANGPTL4 is important in the development and progression of atherosclerosis, and knockout of ANGPTL4 prohibited the progress of atherosis (11). Cellular permeability has profound effects on atherosclerosis.…”

mentioning

confidence: 95%

“…Cellular permeability has profound effects on atherosclerosis. However, the mechanism by which ANGPTL4 promotes atherosis is not known (11,12). Adachi et al (11) found that ANGPTL4 deficiency improves lipid metabolism, suppresses foam cell formation and protects against atherosclerosis in genetic knockout mice.…”

mentioning

confidence: 99%

“…However, the mechanism by which ANGPTL4 promotes atherosis is not known (11,12). Adachi et al (11) found that ANGPTL4 deficiency improves lipid metabolism, suppresses foam cell formation and protects against atherosclerosis in genetic knockout mice. Xu et al (13) found that ANGPTL4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice.…”

mentioning

confidence: 99%

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Advanced glycation end products upregulate angiopoietin-like protein 4 expression by activating the renin-angiotensin system in endothelial cells

et al. 2015

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Abstract. The aim of the present study was to investigate the effects of advanced glycation end products (AGEs) on the expression of angiopoietin-like protein 4 (ANGPTL4) and the mechanisms of the effects in endothelial cells. Endothelial cells were incubated with various concentrations of AGEs for 24 h and the expression of ANGPTL4 was detected by quantitative polymerase chain reaction and western blot analysis. The concentration of angiotensin Ⅱ (Ang Ⅱ) in conditioned media and cell lysates was measured by enzyme-linked immunosorbent assays. Fluorescein isothiocyanate-labeled dextran filtration assays and transendothelial electrical resistance were performed to evaluate endothelial permeability. AGEs (80 µg/ml) increased the expression of ANGPTL4 and the levels of Ang Ⅱ (P<0.05). Incubation with AGEs also resulted in a significant increase in endothelial permeability (P<0.05). However, pretreatment with the Ang Ⅱ receptor blocker losartan (10 -5 M) reduced the effects of AGEs (P<0.05). AGEs upregulated the expression of ANGPTL4 by activating a local renin-angiotensin system in endothelial cells. This may be a new mechanism by which AGEs increase endothelial permeability.

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Angptl 4 deficiency improves lipid metabolism, suppresses foam cell formation and protects against atherosclerosis

Cited by 76 publications

References 22 publications

Emerging Roles of Angiopoietin-like 4 in Human Cancer

Emerging Roles of Angiopoietin-like 4 in Human Cancer

Proteolytic Processing of Angiopoietin-like Protein 4 by Proprotein Convertases Modulates Its Inhibitory Effects on Lipoprotein Lipase Activity

Advanced glycation end products upregulate angiopoietin-like protein 4 expression by activating the renin-angiotensin system in endothelial cells

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