A lipasin/Angptl8 monoclonal antibody lowers mouse serum triglycerides involving increased postprandial activity of the cardiac lipoprotein lipase

Fu, Zhiyao; Abou‐Samra, Abdul Badi; Ren, Zhen

doi:10.1038/srep18502

Cited by 78 publications

(88 citation statements)

References 63 publications

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“…2e, whereas Angptl4 is upregulated due to the elevated circulating glucocorticoid levels34. On one hand, reduced amounts of the Angptl8 protein augments LPL activity specifically in heart and skeletal muscles35, and thus promotes the hydrolysis of VLDL-TG to result in the increased circulating NEFA concentrations. On the other hand, increased amounts of Angptl4 protein decreases LPL activity in an adipose-specific manner36, and promotes intracellular lipolysis in adipocytes37.…”

Section: Discussionmentioning

confidence: 99%

Fasting and Feeding Signals Control the Oscillatory Expression of Angptl8 to Modulate Lipid Metabolism

Dang

Wang

et al. 2016

Sci Rep

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Emerging evidence implies a key role of angiopoietin-like protein 8 (Angptl8) in the metabolic transition between fasting and feeding, whereas much less is known about the mechanism of its own expression. Here we show that hepatic Angptl8 is rhythmically expressed, which involving the liver X receptor alpha (LXRα) and glucocorticoid receptor (GR) modulation during feeding and fasting periods, respectively. In addition, Angptl8 mRNA is very unstable, which contributes to the nature of its daily rhythmicity by rapidly responding to fasting/feeding transition. To explore its pathological function in dexamethasone (DEX)-induced fatty liver, we reversed its suppression by glucocorticoids through adenoviral delivery of Angptl8 gene in mouse liver. Surprisingly, hepatic overexpression of Angptl8 dramatically elevated plasma triglyceride (TG) and non-esterified fatty acid (NEFA) levels in DEX-treated mice, suggesting a metabolic interaction between Angptl8 and glucocorticoid signaling. Moreover, intracellular hepatic Angptl8 is implicated in the regulation of lipid homeostasis by the experiments with ectopic expression of a nonsecreted Angptl8 mutant (Δ25-Angptl8). Altogether, our data demonstrate the molecular mechanism of the diurnal rhythm of Angptl8 expression regulated by glucocorticoid signaling and LXRα pathway, and provide new evidence to understand the role of Angptl8 in maintaining plasma TG homeostasis.

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Section: Discussionmentioning

confidence: 99%

Fasting and Feeding Signals Control the Oscillatory Expression of Angptl8 to Modulate Lipid Metabolism

Dang

Wang

et al. 2016

Sci Rep

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“…Based on its role in lipid regulation, ANGPTL8 has been also suggested as a potential therapeutic target for dyslipidemia. 21,68 In addition, because the ANGPTL8 level has been shown to be increased in obesity and in people with MetS 46 we evaluated the potential association between ANGPTL8 and low-grade inflammation and found a positive association between ANGPTL8 and hsCRP. 46 A positive association between ANGPTL8 and hsCRP has been also found in women diagnosed with polycystic ovary syndrome.…”

Section: Angtpl8 and Its Interaction With Other Biomarkersmentioning

confidence: 99%

ANGPTL8 (betatrophin) role in diabetes and metabolic diseases

Abu‐Farha

Abubaker

Tuomilehto

2017

Diabetes Metabolism Res

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Diabetes is a major disease worldwide that is reaching epidemic levels. Its increased prevalence as well as its association with a high number of complications such as cardiovascular diseases, nephropathy, and retinopathy makes it an important disease for investigation. ANGPTL8 is a recently identified hormone that has been associated with two functionally important processes in the development of type 2 diabetes, insulin resistance as well as lipid metabolism. Initial work has shown that ANGPTL8 was expressed in liver, white adipose, and brown adipose tissues. ANGPTL8 regulates the activity of lipoprotein lipase, which is a key enzyme in lipoprotein lipolysis pathway through its direct interaction with ANGPTL3. It has been also reported that it regulates the replication of β-cells in response to insulin resistance. As a result, many recent studies have focused on the association of ANGPTL8 with diabetes and obesity as well as its association with various metabolic markers in order to better understand its physiological role in glucose homeostasis and lipid metabolism. In this review, we will highlight some of the key clinical findings, mainly from human studies, that investigated the role of ANGPTL8 in metabolic diseases such as diabetes, obesity, and the metabolic syndrome.

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“…Whole-body ANGPTL8 knockout mice (ANGPTL8 -/-, B6; 129S5-Angptl8 tm1Lex /Mmucd) were a gift from Dr. Ren Zhang at Wayne State University (Michigan, USA) and were originally obtained from the Mutant Mouse Resource Research Centers (7). Mice were fed either regular chow or a high-fat diet (HFD; Research Diets, D12492), where indicated.…”

Section: Angptl8 Knockout Micementioning

confidence: 99%

The Metabolic Effects of Angiopoietin-like protein 8 (ANGPLT8) are Differentially Regulated by Insulin and Glucose in Adipose Tissue and Liver and are Controlled by AMPK Signaling

Zhang

Shannon

Bakewell

et al. 2019

Preprint

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Objective:The angiopoietin-like protein (ANGPTL) family represents a promising therapeutic target for dyslipidemia, which is a feature of obesity and type 2 diabetes (T2DM). The aim of the present study was to determine the metabolic role of ANGPTL8 and to investigate its nutritional, hormonal and molecular regulation in key metabolic tissues. Methods:The metabolism of ANGPTL8 knockout mice (ANGPTL8 -/-) was examined in mice following chow and high-fat diets (HFD). The regulation of ANGPTL8 expression by insulin and glucose was quantified using a combination of in vivo insulin clamp experiments in mice and in vitro experiments in hepatocytes and adipocytes. The role of AMPK signaling was examined, and the transcriptional control of ANGPTL8 was determined using bioinformatic and luciferase reporter approaches. Results:The ANGPTL8 -/mice had improved glucose tolerance and displayed reduced fed and fasted plasma triglycerides. However, there was no reduction in steatosis in ANGPTL8 -/mice after the HFD.Insulin acutely activated ANGPTL8 expression in liver and adipose tissue, which was mediated by C/EBPβ. Using insulin clamp experiments we observed that glucose further enhanced ANGPTL8 expression in the presence of insulin in adipocytes only. The activation of AMPK signaling potently suppressed the effect of insulin on ANGPTL8 expression in hepatocytes. Conclusion:These data show that ANGPTL8 plays an important metabolic role in mice that may extend beyond triglyceride metabolism. The finding that insulin and glucose have distinct roles in regulating ANGPTL8 expression in liver and adipose tissue may provide important clues about the function of ANGPTL8 in these tissues.

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A lipasin/Angptl8 monoclonal antibody lowers mouse serum triglycerides involving increased postprandial activity of the cardiac lipoprotein lipase

Cited by 78 publications

References 63 publications

Fasting and Feeding Signals Control the Oscillatory Expression of Angptl8 to Modulate Lipid Metabolism

Fasting and Feeding Signals Control the Oscillatory Expression of Angptl8 to Modulate Lipid Metabolism

ANGPTL8 (betatrophin) role in diabetes and metabolic diseases

The Metabolic Effects of Angiopoietin-like protein 8 (ANGPLT8) are Differentially Regulated by Insulin and Glucose in Adipose Tissue and Liver and are Controlled by AMPK Signaling

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