Inhibition of Angiopoietin-Like Protein 3 With a Monoclonal Antibody Reduces Triglycerides in Hypertriglyceridemia

Ahmad, Zahid; Banerjee, Poulabi; Hamon, Sara; Chan, Kuo‐Chen; Bouzelmat, Aurelie; Sasiela, William J.; Pordy, Robert; Mellis, Scott; Dansky, Hayes M.; Gipe, Daniel A.; Dunbar, Richard L.

doi:10.1161/circulationaha.118.039107

Cited by 187 publications

(151 citation statements)

References 47 publications

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“…The biological importance of ANGPTLs in regulating plasma triglyceride homeostasis by inhibiting LPL activity has been firmly established by human and mouse genetics (15)(16)(17)(18)(19) and by pharmacological studies (7,(45)(46)(47), but the molecular mechanism for LPL inactivation has remained controversial. One view holds that ANGTPL4 is a reversible and noncompetitive LPL inhibitor with an inhibition constant (K i ) of 0.9 to 1.7 μM (48,49), but that view relies on studies performed in the presence of deoxycholate (a detergent that stabilizes LPL) (4,50).…”

Section: Discussionmentioning

confidence: 99%

Unfolding of monomeric lipoprotein lipase by ANGPTL4: Insight into the regulation of plasma triglyceride metabolism

Kristensen

Leth-Espensen

Mertens

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The binding of lipoprotein lipase (LPL) to GPIHBP1 focuses the intravascular hydrolysis of triglyceride-rich lipoproteins on the surface of capillary endothelial cells. This process provides essential lipid nutrients for vital tissues (e.g., heart, skeletal muscle, and adipose tissue). Deficiencies in either LPL or GPIHBP1 impair triglyceride hydrolysis, resulting in severe hypertriglyceridemia. The activity of LPL in tissues is regulated by angiopoietin-like proteins 3, 4, and 8 (ANGPTL). Dogma has held that these ANGPTLs inactivate LPL by converting LPL homodimers into monomers, rendering them highly susceptible to spontaneous unfolding and loss of enzymatic activity. Here, we show that binding of an LPL-specific monoclonal antibody (5D2) to the tryptophan-rich lipid-binding loop in the carboxyl terminus of LPL prevents homodimer formation and forces LPL into a monomeric state. Of note, 5D2-bound LPL monomers are as stable as LPL homodimers (i.e., they are not more prone to unfolding), but they remain highly susceptible to ANGPTL4-catalyzed unfolding and inactivation. Binding of GPIHBP1 to LPL alone or to 5D2-bound LPL counteracts ANGPTL4-mediated unfolding of LPL. In conclusion, ANGPTL4-mediated inactivation of LPL, accomplished by catalyzing the unfolding of LPL, does not require the conversion of LPL homodimers into monomers. Thus, our findings necessitate changes to long-standing dogma on mechanisms for LPL inactivation by ANGPTL proteins. At the same time, our findings align well with insights into LPL function from the recent crystal structure of the LPL•GPIHBP1 complex.

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Section: Discussionmentioning

confidence: 99%

Unfolding of monomeric lipoprotein lipase by ANGPTL4: Insight into the regulation of plasma triglyceride metabolism

Kristensen

Leth-Espensen

Mertens

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…While additional lipid-lowering strategies are required to achieve sufficient LDL-lowering in the general population, LDLR-independent pathways for patients lacking functional LDLR represent a particularly urgent need for therapeutic intervention. 5 administered subcutaneously or intravenously to participants with varying degrees of dyslipidemia (28) (ClinicalTrials.gov Identifier: NCT01749878). Part of the results for Group A of this trial are described in this report.…”

Section: Introductionmentioning

confidence: 99%

Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance

Adam

Mintah

Alexa-Braun

et al. 2020

Journal of Lipid Research

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140

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Angiopoietin-like protein 3 (ANGPTL3) regulates plasma lipids by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL). ANGPTL3 inactivation lowers LDL-cholesterol (LDL-C) independently of the classical LDL-receptor (LDLR)-mediated pathway and represents a promising therapeutic approach for individuals with homozygous familial hypercholesterolemia due to LDLR mutations. Yet, how ANGPTL3 regulates LDL-C levels is unknown. Here, we demonstrate in hyperlipidemic humans and mice that ANGPTL3 controls VLDL catabolism upstream of LDL. Using kinetic, lipidomic and biophysical studies, we show that ANGPTL3 inhibition reduces VLDL-lipid content and size, generating remnant particles that are efficiently removed from the circulation. This suggests that ANGPTL3 inhibition lowers LDL-C by limiting LDL particle production. Mechanistically, we discovered that EL is a key mediator of ANGPTL3’s novel pathway. Our experiments revealed that, although dispensable in the presence of LDLR, EL-mediated processing of VLDL becomes critical for LDLR-independent particle clearance. In the absence of EL and LDLR, ANGPTL3 inhibition perturbed VLDL catabolism, promoted accumulation of atypical remnants, and failed to reduce LDL-C. Taken together, we uncover ANGPTL3 at the helm of a novel EL-dependent pathway that lowers LDL-C in the absence of LDLR.

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“…Inactivation of ANGPTL4 using a monoclonal antibody was first shown to lower triglyceride levels by about 50% in primates, but side effects blocked further development and attention has turned to inhibition of ANGPTL3. The monoclonal antibody evinacumab that blocks the action of ANGPTL3 has been found to lower triglyceride levels up to 80% in patients with mild to moderate HTG and also lowers LDL-C (132,134). Of further importance is the possibility that both apo C-III as well as ANGPTL3 lowering may lead to reduction in CVD risk (135).…”

Section: Targeting Lpl Regulatorsmentioning

confidence: 99%

A Comprehensive Update on the Chylomicronemia Syndrome

Goldberg

Chait

2020

Front. Endocrinol.

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The chylomicronemia syndrome is characterized by severe hypertriglyceridemia and fasting chylomicronemia and predisposes affected individuals to acute pancreatitis. When due to very rare monogenic mutations in the genes encoding the enzyme, lipoprotein lipase, or its regulators, APOC2, APOA5, GPIHBP1, and LMF1, it is referred to as the familial chylomicronemia syndrome. Much more frequently, the chylomicronemia syndrome results from a cluster of minor genetic variants causing polygenic hypertriglyceridemia, which is exacerbated by conditions or medications which increase triglyceride levels beyond the saturation point of triglyceride removal systems. This situation is termed the multifactorial chylomicronemia syndrome. These aggravating factors include common conditions such as uncontrolled diabetes, overweight and obesity, alcohol excess, chronic kidney disease and pregnancy and several medications, including diuretics, non-selective beta blockers, estrogenic compounds, corticosteroids, protease inhibitors, immunosuppressives, antipsychotics, antidepressants, retinoids, L-asparaginase, and propofol. A third uncommon cause of the chylomicronemia syndrome is familial forms of partial lipodystrophy. Development of pancreatitis is the most feared complication of the chylomicronemia syndrome, but the risk of cardiovascular disease as well as non-alcoholic steatohepatitis is also increased. Treatment consists of dietary fat restriction and weight reduction combined with the use of triglyceride lowering medications such as fibrates, omega 3 fatty acids and niacin. Effective management of aggravating factors such as improving diabetes control, discontinuing alcohol and replacing or reducing the dose of medications that raise triglyceride levels is essential. Importantly, many if not most cases of the chylomicronemia syndrome can be prevented by effective identification of polygenic hypertriglyceridemia in people with conditions that increase its likelihood or before starting medications that may increase triglyceride levels. Several new pharmacotherapeutic agents are being tested that are likely to considerably improve treatment of hypertriglyceridemia in people at risk.

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Inhibition of Angiopoietin-Like Protein 3 With a Monoclonal Antibody Reduces Triglycerides in Hypertriglyceridemia

Abstract: Supplemental Digital Content is available in the text.

Cited by 187 publications

References 47 publications

Unfolding of monomeric lipoprotein lipase by ANGPTL4: Insight into the regulation of plasma triglyceride metabolism

Unfolding of monomeric lipoprotein lipase by ANGPTL4: Insight into the regulation of plasma triglyceride metabolism

Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance

A Comprehensive Update on the Chylomicronemia Syndrome

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