Metreleptin therapy lowers plasma angiopoietin-like protein 3 in patients with generalized lipodystrophy

Muniyappa, Ranganath; Abel, Brent S.; Asthana, Asha; Walter, Mary; Cochran, Elaine; Remaley, Alan T.; Skarulis, Monica C.; Görden, Phillip; Brown, Rebecca

doi:10.1016/j.jacl.2017.02.002

Cited by 20 publications

(14 citation statements)

References 31 publications

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“…Metreleptin may disrupt events that lead to lipotoxicity, as improvements in hepatic and intramyocellular lipid content, liver volume and steatohepatitis have occurred with the drug in LD patients [5,9]. Elevated levels of apolipoprotein CII and ANGPTL3 (proteins that inhibit lipoprotein lipase) in patients with LD may contribute to hypertriglyceridaemia, with levels of ANGPTL3 (but not apolipoprotein CII) being reduced by metreleptin [16,17]. Reductions in plasma levels of PCSK9 (a protein that promotes hypercholesterolaemia) have also been seen with metreleptin in LD patients, with a decline in creatinine clearance (likely indicating reduced glomerular hyperfiltration) [24].…”

Section: How Does Metreleptin Work?mentioning

confidence: 99%

Metreleptin in lipodystrophy: a profile of its use

Deeks

2019

Drugs Ther Perspect

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Metreleptin [Myalepta ® (EU); Myalept ® (USA)] is a recombinant analogue of human leptin and currently the only drug available for the specific treatment of lipodystrophy (LD). In the EU, metreleptin (administered once daily via subcutaneous injection) is indicated as replacement therapy to treat the complications of leptin deficiency in patients aged ≥ 2 years with generalized LD and in patients aged ≥ 12 years with partial LD who have failed to achieve adequate metabolic control with standard treatments. Its use in these rare settings is supported by data from open-label clinical studies and clinical practice, with the totality of evidence indicating that metreleptin improves metabolic abnormalities associated with generalized or partial LD, including in paediatric patients. Other potential benefits include improved hepatic parameters/disease, nephropathy and survival, although the impact of the drug on these outcomes would benefit from further analysis. Metreleptin is generally well tolerated.

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Section: How Does Metreleptin Work?mentioning

confidence: 99%

Metreleptin in lipodystrophy: a profile of its use

Deeks

2019

Drugs Ther Perspect

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“…Recently, Muniyappa et al [ 115 ] found that patients affected by lipodystrophy treated with metreleptin showed a marked reduction in circulating ANGPTL3 levels together with a consistent improvement in liver steatosis, whereas ANGPTL4 levels remained unchanged [ 115 ].…”

Section: Clinical Conditions Linking Angptls and Adipose Tissue Dymentioning

confidence: 99%

The Interplay between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship between Adiposopathy and Cardiometabolic Diseases?

Bini

D’Erasmo

Costanzo

et al. 2021

IJMS

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Angiopoietin-like proteins, namely ANGPTL3-4-8, are known as regulators of lipid metabolism. However, recent evidence points towards their involvement in the regulation of adipose tissue function. Alteration of adipose tissue functions (also called adiposopathy) is considered the main inducer of metabolic syndrome (MS) and its related complications. In this review, we intended to analyze available evidence derived from experimental and human investigations highlighting the contribution of ANGPTLs in the regulation of adipocyte metabolism, as well as their potential role in common cardiometabolic alterations associated with adiposopathy. We finally propose a model of ANGPTLs-based adipose tissue dysfunction, possibly linking abnormalities in the angiopoietins to the induction of adiposopathy and its related disorders.

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“…The role leptin on ANGPTL3 expression and plasma level in humans was recently documented in a study [39] conducted in patients with generalized lipodystrophy, a leptin deficient condition associated with hypertriglyceridemia [40] . These patients were found to have increased plasma levels of ANGPTL3 (but not plasma levels of ANGPTL4), suggesting the possibility that hypertriglyceridemia might be the result of ANGPTL3 mediated inhibition of LPL [39] . After metreleptin treatment, the plasma level of leptin increased whereas the plasma level of ANGPTL3 and TG showed a significant decrease [39] .…”

Section: Angptl3 and Metabolic Conditions Associated With Hypertriglymentioning

confidence: 99%

“…These patients were found to have increased plasma levels of ANGPTL3 (but not plasma levels of ANGPTL4), suggesting the possibility that hypertriglyceridemia might be the result of ANGPTL3 mediated inhibition of LPL [39] . After metreleptin treatment, the plasma level of leptin increased whereas the plasma level of ANGPTL3 and TG showed a significant decrease [39] . Thus, the finding of elevated ANGPTL3 levels in patients with lipodystrophy and their reduction following leptin treatment is consistent with the results obtained in leptin deficient mice and suggests that ANGPTL3 may contribute to hypertriglyceridemia in leptin deficient states.…”

Section: Angptl3 and Metabolic Conditions Associated With Hypertriglymentioning

confidence: 99%

Angiopoietin-like protein 3 (ANGPTL3) deficiency and familial combined hypolipidemia

2019

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Three members of the angiopoietin-like (ANGPTL) protein family-ANGPTL3, ANGPTL4 and ANGPTL8- are important regulators of plasma lipoproteins. They inhibit the enzyme lipoprotein lipase, which plays a key role in the intravascular lipolysis of triglycerides present in some lipoprotein classes. This review focuses on the role of ANGPTL3 as emerged from the study of genetic variants of Angptl3 gene in mice and humans. Both loss of function genetic variants and inactivation of Angptl3 gene in mice are associated with a marked reduction of plasma levels of triglyceride and cholesterol and an increased activity of lipoprotein lipase and endothelial lipase. In humans with ANGPTL3 deficiency, caused by homozygous loss of function (LOF) variants of Angptl3 gene, the levels of all plasma lipoproteins are greatly reduced. This plasma lipid disorder referred to as familial combined hypolipidemia (FHBL2) does not appear to be associated with distinct pathological manifestations. Heterozygous carriers of LOF variants have reduced plasma levels of total cholesterol and triglycerides and are at lower risk of developing atherosclerotic cardiovascular disease, as compared to non-carriers. These observations have paved the way to the development of strategies to reduce the plasma level of atherogenic lipoproteins in man by the inactivation of ANGPTL3, using either a specific monoclonal antibody or anti-sense oligonucleotides.

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Metreleptin therapy lowers plasma angiopoietin-like protein 3 in patients with generalized lipodystrophy

Cited by 20 publications

References 31 publications

Metreleptin in lipodystrophy: a profile of its use

Metreleptin in lipodystrophy: a profile of its use

The Interplay between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship between Adiposopathy and Cardiometabolic Diseases?

Angiopoietin-like protein 3 (ANGPTL3) deficiency and familial combined hypolipidemia

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