Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis

Aryal, Binod; Singh, Abhishek Kumar; Zhang, Xinbo; Varela, Luis; Rotllan, Noemí; Goedeke, Leigh; Chaube, Balkrishna; Camporez, João-Paulo G.; Vatner, Daniel F.; Horváth, Tamas L.; Shulman, Gerald I.; Suárez, Yajaira; Fernández‐Hernando, Carlos

doi:10.1172/jci.insight.97918

Cited by 107 publications

(123 citation statements)

References 63 publications

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“…We have observed that adipose-specific ANGPTL4 knockout (Ad-KO) mice displayed reduced circulating TAG levels, similar to what was observed in humans with a missense mutation in ANGPTL4 (E40K variant). However, other factors identified in this study such as body weight and regulation of glucose homeostasis, were unaltered after chronic administration of HFD feeding (32). These findings suggest that ANGPTL4 in other tissues, such as the liver, could also play a key role in the regulation of whole-body metabolism.…”

Section: Introductionmentioning

confidence: 54%

“…Our recent work has demonstrated an essential role for adipose-derived ANGPTL4 in regulating lipid uptake and regulation of metabolic function by AT (32). We have observed that adipose-specific ANGPTL4 knockout (Ad-KO) mice displayed reduced circulating TAG levels, similar to what was observed in humans with a missense mutation in ANGPTL4 (E40K variant).…”

Section: Introductionmentioning

confidence: 65%

“…Since ANGPTL4 is highly expressed in the liver and AT of both humans and mice, we generated ANGPTL4 knockout mouse models specific to these issues. We have previously reported that adipose-specific ANGPTL4 knockout (Ad-KO) mice exhibit improved plasma lipid profiles and insulin sensitivity, but no difference in body weight between Ad-KO and WT mice during prolonged HFD feeding (32 It has been previously reported that HL, in addition to acting as a lipolytic enzyme, also facilitates the uptake of chylomicrons and VLDL remnants by hepatocyte cell surface receptors, thus lowering circulating lipids (44,45). Comparison of FPLC plasma lipoprotein cholesterol profiles (IDL/LDL-fraction) in atherogenic mice further indicates that the protective impact of hepatic depletion of ANGPTL4 involves the contribution of elevated HL activity.…”

Section: Discussionmentioning

confidence: 99%

“…The reduction in fat mass and size of adipocytes in LKO mice could be due to the accelerated hydrolysis of TRL remnants and increased FA uptake in the liver, decreasing circulating TAGs and thereby reducing lipid storage in AT. The role of ANGPTL4 in the regulation of body weight in mice has been controversial under both physiological as well as pathophysiological conditions (13,21,28,32). The different outcomes from these studies may be due to the inactivation of different exons of the N-terminus of ANGPTL4 in the different knockout models, different types of diet, and the magnitude of overexpression.…”

Section: Discussionmentioning

confidence: 99%

“…Generation of liver-specific ANGPTL4-deficient mice. Mice bearing a loxP-flanked ANGPTL4 allele (ANGPTL4 loxP/loxP mice) were generated as described previously (32).…”

Section: Animal Studiesmentioning

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: Introductionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Generation of liver-specific ANGPTL4-deficient mice. Mice bearing a loxP-flanked ANGPTL4 allele (ANGPTL4 loxP/loxP mice) were generated as described previously (32).…”

Section: Animal Studiesmentioning

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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The Regulation of Triacylglycerol Metabolism and Lipoprotein Lipase Activity

2022

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Triacylglycerol (TG) metabolism is tightly regulated to maintain a pool of TG within circulating lipoproteins that can be hydrolyzed in a tissue‐specific manner by lipoprotein lipase (LPL) to enable the delivery of fatty acids to adipose or oxidative tissues as needed. Elevated serum TG concentrations, which result from a deficiency of LPL activity or, more commonly, an imbalance in the regulation of tissue‐specific LPL activities, have been associated with an increased risk of atherosclerotic cardiovascular disease through multiple studies. Among the most critical LPL regulators are the angiopoietin‐like (ANGPTL) proteins ANGPTL3, ANGPTL4, and ANGPTL8, and a number of different apolipoproteins including apolipoprotein A5 (ApoA5), apolipoprotein C2 (ApoC2), and apolipoprotein C3 (ApoC3). These ANGPTLs and apolipoproteins work together to orchestrate LPL activity and therefore play pivotal roles in TG partitioning, hydrolysis, and utilization. This review summarizes the mechanisms of action, epidemiological findings, and genetic data most relevant to these ANGPTLs and apolipoproteins. The interplay between these important regulators of TG metabolism in both fasted and fed states is highlighted with a holistic view toward understanding key concepts and interactions. Strategies for developing safe and effective therapeutics to reduce circulating TG by selectively targeting these ANGPTLs and apolipoproteins are also discussed.

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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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Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis

Cited by 107 publications

References 63 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

The Regulation of Triacylglycerol Metabolism and Lipoprotein Lipase Activity

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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