Plasma ANGPTL‐4 is Associated with Obesity and Glucose Tolerance: Cross‐Sectional and Longitudinal Findings

Barja-Fernández, Silvia; Moreno-Navarrete, José María; Folgueira, Cintia; Xifra, Gemma; Sabater, Mònica; Castelao, Cecilia; Fernø, Johan; Leis, Rosaura; Diéguez, Carlos; Casanueva, Felipe F.; Ricart, Wifredo; Seoane, Luísa M.; Fernández‐Real, José Manuel; Nogueiras, Rubén

doi:10.1002/mnfr.201800060

Cited by 36 publications

(42 citation statements)

References 34 publications

(54 reference statements)

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“…Elevated circulating levels of ANGPTL4 and TAGs are key etiologic components of metabolic disorders like obesity, T2D, and CAD, which are associated with increased adiposity, fatty liver, and insulin resistance. Human studies indicate a positive relationship between ANGPTL4 function and body mass index (BMI), fat mass, glucose intolerance, insulin resistance, and circulating lipids (25). These observations strongly suggest that ANGPTL4 could be a potential target in metabolic diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies in humans have shown that loss of function mutations in the ANGPTL4 locus are associated with reduced type 2 diabetes and risk of cardiovascular disease (21,25). However, mice lacking ANGPTL4 and fed a high fat diet enriched in saturated fat develop gut inflammation, characterized by the accumulation of lipid-laden macrophages.…”

Section: Galnac-conjugated Angptl4 Aso Treatment Improves Body Weightmentioning

confidence: 99%

“…Post-heparin plasma was collected as previously described (25). Enzymatic activity of hepatic lipase and post-heparin lipoprotein lipase was determined by using 3 H-labeled triolein according to the protocol described previously (32,50).…”

Section: Lpl and Hl Activity Assaymentioning

confidence: 99%

“…Human genetics and clinical studies have emphatically demonstrated that mutations in the ANGPTL4 gene (E40K) are associated with reduced plasma TAG and glucose levels (21)(22)(23)(24). Importantly, the circulating level of ANGPTL4 is positively correlated with increased risk of cardiovascular disease (CVD) and T2D, along with obesity-associated diabetic phenotypes such as high BMI, fat mass, and altered glucose homeostasis (25). These observations indicate that ANGPTL4 is strongly implicated in the development of metabolic diseases in humans; however, the underlying molecular mechanism is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Liver-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice

Singh

Chaube

Canfrán‐Duque

et al. 2020

Preprint

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Angiopoietin-like 4 (ANGPTL4) is a major regulator of lipoprotein lipase (LPL) activity, which is responsible for maintaining optimal levels of circulating triacylglycerol (TAG) for distribution to different tissues including the adipose tissues (ATs), heart, muscle and liver. Dysregulation of trafficking and portioning of fatty acids (FA) can promote ectopic lipid accumulation in metabolic tissues such as the liver, ultimately leading to systemic metabolic dysfunction. To investigate how ANGPTL4 regulates hepatic lipid and glucose metabolism, we generated liver-specific ANGPTL4 knockout mice (LKO). Using metabolic turnover studies, we demonstrate that hepatic ANGPTL4 deficiency facilitates catabolism of TAG-rich lipoprotein (TRL) remnants in the liver via increased hepatic lipase (HL) activity, which results in a significant reduction in circulating TAG and cholesterol levels. Deletion of hepatocyte ANGPTL4 protects against diet-induce obesity, glucose intolerance, liver steatosis, and atherogenesis. Mechanistically, we demonstrate that absence of ANGPTL4 in hepatocytes promotes FA uptake which results in increased FA oxidation, ROS production, and AMPK activation. Finally, we demonstrate the utility of a targeted pharmacologic therapy that specifically inhibits ANGPTL4 in the liver and protects against diet-induced obesity, dyslipidemia, glucose intolerance, and liver damage without causing any of the deleterious effects previously observed with neutralizing antibodies.

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Section: Discussionmentioning

confidence: 99%

Section: Galnac-conjugated Angptl4 Aso Treatment Improves Body Weightmentioning

confidence: 99%

Section: Lpl and Hl Activity Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Liver-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice

Singh

Chaube

Canfrán‐Duque

et al. 2020

Preprint

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“…Angiopoietin-like protein 4 (ANGPTL4) was first discovered in 2000 [5] as a novel member of the angiopoietin family. Under physiological conditions, ANGPTL4 functions as a key regulator of lipid metabolism and its role has been widely reported in metabolic diseases and cardiovascular diseases [6,7]. In addition, some studies have reported that ANGPTL4 plays a significant role in tumor invasion, intestinal microecological regulation, fracture healing, and tendon cell proliferation, adhesion, and migration [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Alteration of Angiopoietin-Like Protein 4 Levels in Serum or Urine Correlate with Different Biochemical Markers in Hyperlipidemia-Related Proteinuria

Gao

Zhang

Feng

et al. 2020

BioMed Research International

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Angiopoietin-like protein 4 (ANGPTL4) is widely known as a key regulator of lipid metabolism. We investigated the relationship between ANGPTL4 expression in serum or urine and blood lipid or urine protein levels of patients with hyperlipidemia- (HL-) related proteinuria. Sixty-eight patients with HL-related proteinuria (HL-Pro group), 68 patients with HL without proteinuria (HL-NPro group), 46 patients with non-HL-related proteinuria (NHL-Pro group), and 50 healthy control (Con) subjects were selected. There were no significant differences in serum ANGPTL4 levels between the Con group (36.82±17.03 ng/ml) and the HL-Pro group (27.94 (18.90, 53.72) ng/ml). Additionally, the serum ANGPTL4 levels in the HL-Pro group were significantly lower than those in the HL-NPro group (53.32±24.01 ng/ml) (P<0.001). The urine ANGPTL4/Cr levels in the HL-Pro group (52.01 (45.25, 79.79) μg/g) were significantly higher than those in the HL-NPro group (9.96 (8.35, 12.43) ng/ml) (P<0.05). A significant alteration in urine ANGPTL4/Cr levels was observed in the NHL-Pro group (69.41±55.36 μg/g) and the Con group (10.08±2.38 μg/g) as well. There was no correlation between serum and urine ANGPTL4 levels of the four groups (P>0.05). Serum ANGPTL4 levels (HL-Pro/HL-NPro group) were positively correlated with total cholesterol (TC) and triglyceride (TG) levels in hyperlipidemia patients. However, there was no correlation between urinary ANGPTL4 levels and TC or TG (P>0.05). Urine ANGPTL4 levels were positively correlated with 24hUPro in patients with renal impairment (HL-Pro/NHL-Pro group). To summarize, ANGPTL4 may be considered an accurate predictor of proteinuria with HL. Notably, serum or urine ANGPTL4 levels indicated the degree of proteinuria or hyperlipidemia, respectively, in HL patients.

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Angiopoietin‐like protein 4 induces growth hormone variant secretion and aggravates insulin resistance during pregnancy, linking obesity to gestational diabetes mellitus

Kuo,

Wang,

Juan

et al. 2024

BioFactors

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Angiopoietin‐like protein 4 (ANGPTL4) is a secretory glycoprotein involved in regulating glucose homeostasis in non‐pregnant subjects. However, its role in glucose metabolism during pregnancy and the pathophysiology of gestational diabetes mellitus (GDM) remains elusive. Thus, this study aimed to clarify the relationship between ANGPTL4 and GDM and investigate the pathophysiology of placental ANGPTL4 in glucose metabolism. We investigated this issue using blood and placenta samples in 957 pregnant women, the human 3A‐sub‐E trophoblast cell line, and the L6 skeletal muscle cell line. We found that ANGPTL4 expression in the placenta was higher in obese pregnant women than in lean controls. Palmitic acid significantly induced ANGPTL4 expression in trophoblast cells in a dose–response manner. ANGPTL4 overexpression in trophoblast cells resulted in endoplasmic reticulum (ER) stress, which stimulated the expression and secretion of growth hormone‐variant (GH2) but not human placental lactogen. In L6 skeletal muscle cells, soluble ANGPTL4 suppressed insulin‐mediated glucose uptake through the epidermal growth factor receptor (EGFR)/extracellular signal‐regulated kinases 1/2 (ERK 1/2) pathways. In pregnant women, plasma ANGPTL4 concentrations in the first trimester predicted the incidence of GDM and were positively associated with BMI, plasma triglyceride, and plasma GH2 in the first trimester. However, they were negatively associated with insulin sensitivity index ISI0,120 in the second trimester. Overall, placental ANGPTL4 is induced by obesity and is involved in the pathophysiology of GDM via the induction of ER stress and GH2 secretion. Soluble ANGPTL4 can lead to insulin resistance in skeletal muscle cells and is an early biomarker for predicting GDM.

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Plasma ANGPTL‐4 is Associated with Obesity and Glucose Tolerance: Cross‐Sectional and Longitudinal Findings

Abstract: Our data support a relevant role of ANGPTL-4 in human obesity and its involvement in long-term body weight changes.

Cited by 36 publications

References 34 publications

Liver-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice

Liver-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice

Alteration of Angiopoietin-Like Protein 4 Levels in Serum or Urine Correlate with Different Biochemical Markers in Hyperlipidemia-Related Proteinuria

Angiopoietin‐like protein 4 induces growth hormone variant secretion and aggravates insulin resistance during pregnancy, linking obesity to gestational diabetes mellitus

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