The Angiopoietin-Like Protein 3 and 8 Complex Interacts with Lipoprotein Lipase and Induces LPL Cleavage

Jin, Najia; Matter, William F.; Michael, Laura F.; Qian, Yue‐Wei; Gheyi, T.; Cano, Leticia; Perez, Carlos A.; Lafuente, C. B.; Broughton, Howard B.; Espada, Alfonso

doi:10.1021/acschembio.0c00954

Cited by 26 publications

(23 citation statements)

References 28 publications

(64 reference statements)

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“…Of note, this PCSK3 cleavage of LPL on the cell surface is promoted by ANGPTL3, allegedly even in the presence of GPIHBP1. Both inhibition of LPL activity and sensitization to PCSK3 cleavage was enhanced by the ANGPTL3-ANGPTL8 complex (Jin et al, 2021). As judged by HDX-MS, the binding site on LPL for the ANGPTL3-ANGPTL8 complex coincide partly with that delineated for ANGPTL4 (Gutgsell et al, 2019;Jin et al, 2021;Leth-Espensen et al, 2021).…”

Section: Angptl3 Forms An Lpl Inhibitory Complex With Angptl8mentioning

confidence: 86%

“…Both inhibition of LPL activity and sensitization to PCSK3 cleavage was enhanced by the ANGPTL3-ANGPTL8 complex (Jin et al, 2021). As judged by HDX-MS, the binding site on LPL for the ANGPTL3-ANGPTL8 complex coincide partly with that delineated for ANGPTL4 (Gutgsell et al, 2019;Jin et al, 2021;Leth-Espensen et al, 2021). In future studies, it would be interesting to assess by HDX-MS, whether the ANGPTL3-ANGPTL8 complex induces the same allosteric unfolding of LPL as ANGPTL4 and to define the precise roles for ANGPTL3 and ANGPTL8 in binding and inactivation of LPL.…”

Section: Angptl3 Forms An Lpl Inhibitory Complex With Angptl8mentioning

confidence: 97%

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GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity

Kristensen

Leth-Espensen

Kumari

et al. 2021

Front. Cell Dev. Biol.

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Intravascular processing of triglyceride-rich lipoproteins (TRLs) is crucial for delivery of dietary lipids fueling energy metabolism in heart and skeletal muscle and for storage in white adipose tissue. During the last decade, mechanisms underlying focal lipolytic processing of TRLs along the luminal surface of capillaries have been clarified by fresh insights into the functions of lipoprotein lipase (LPL); LPL’s dedicated transporter protein, glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 (GPIHBP1); and its endogenous inhibitors, angiopoietin-like (ANGPTL) proteins 3, 4, and 8. Key discoveries in LPL biology include solving the crystal structure of LPL, showing LPL is catalytically active as a monomer rather than as a homodimer, and that the borderline stability of LPL’s hydrolase domain is crucial for the regulation of LPL activity. Another key discovery was understanding how ANGPTL4 regulates LPL activity. The binding of ANGPTL4 to LPL sequences adjacent to the catalytic cavity triggers cooperative and sequential unfolding of LPL’s hydrolase domain resulting in irreversible collapse of the catalytic cavity and loss of LPL activity. Recent studies have highlighted the importance of the ANGPTL3–ANGPTL8 complex for endocrine regulation of LPL activity in oxidative organs (e.g., heart, skeletal muscle, brown adipose tissue), but the molecular mechanisms have not been fully defined. New insights have also been gained into LPL–GPIHBP1 interactions and how GPIHBP1 moves LPL to its site of action in the capillary lumen. GPIHBP1 is an atypical member of the LU (Ly6/uPAR) domain protein superfamily, containing an intrinsically disordered and highly acidic N-terminal extension and a disulfide bond–rich three-fingered LU domain. Both the disordered acidic domain and the folded LU domain are crucial for the stability and transport of LPL, and for modulating its susceptibility to ANGPTL4-mediated unfolding. This review focuses on recent advances in the biology and biochemistry of crucial proteins for intravascular lipolysis.

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Section: Angptl3 Forms An Lpl Inhibitory Complex With Angptl8mentioning

confidence: 86%

Section: Angptl3 Forms An Lpl Inhibitory Complex With Angptl8mentioning

confidence: 97%

GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity

Kristensen

Leth-Espensen

Kumari

et al. 2021

Front. Cell Dev. Biol.

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“…During feeding, the action of ANGPTL3 is driven by ANGPTL8, which forms a functional ANGPTL3/8 complex to enhance the ANGPTL3-mediated inhibitory effect of LPL activity [ 10 , 42 , 43 ]. Recently, Jin et al reported that ANGPTL3/8 interacts with LPL and promotes furin-mediated LPL cleavage [ 44 ]. More insight into the roles of the ANGPTL3/8 complex and its molecular mechanism of action in LPL inhibition should be provided in molecular modeling studies in the future.…”

Section: Angptl3 and Lipid Metabolismmentioning

confidence: 99%

Angiopoietin-Like Protein 3 (ANGPTL3) Modulates Lipoprotein Metabolism and Dyslipidemia

Chen

Gao

Liou

et al. 2021

IJMS

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Dyslipidemia is characterized by increasing plasma levels of low-density lipoprotein-cholesterol (LDL-C), triglycerides (TGs) and TG-rich lipoproteins (TGRLs) and is a major risk factor for the development of atherosclerotic cardiovascular disorders (ASCVDs). It is important to understand the metabolic mechanisms underlying dyslipidemia to develop effective strategies against ASCVDs. Angiopoietin-like 3 (ANGPTL3), a member of the angiopoietin-like protein family exclusively synthesized in the liver, has been demonstrated to be a critical regulator of lipoprotein metabolism to inhibit lipoprotein lipase (LPL) activity. Genetic, biochemical, and clinical studies in animals and humans have shown that loss of function, inactivation, or downregulated expression of ANGPTL3 is associated with an obvious reduction in plasma levels of TGs, LDL-C, and high-density lipoprotein-cholesterol (HDL-C), atherosclerotic lesions, and the risk of cardiovascular events. Therefore, ANGPTL3 is considered an alternative target for lipid-lowering therapy. Emerging studies have focused on ANGPTL3 inhibition via antisense oligonucleotides (ASOs) and monoclonal antibody-based therapies, which have been carried out in mouse or monkey models and in human clinical studies for the management of dyslipidemia and ASCVDs. This review will summarize the current literature on the important role of ANGPTL3 in controlling lipoprotein metabolism and dyslipidemia, with an emphasis on anti-ANGPTL3 therapies as a potential strategy for the treatment of dyslipidemia and ASCVDs.

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“…In aggregate, these studies show that LPL auto-inactivates by spontaneous unfolding, unless its intrinsic instability is counteracted by binding to GPIHBP1 or HSPG. This weakness is further exploited by ANGPTL3 and ANGPTL4 that inhibit LPL by catalyzing the unfolding of its catalytic domain [65,66].…”

Section: Gpihbp1-binding Render Lpl Stable At Body Temperaturementioning

confidence: 99%

The Importance of Lipoprotein Lipase Regulation in Atherosclerosis

et al. 2021

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Lipoprotein lipase (LPL) plays a major role in the lipid homeostasis mainly by mediating the intravascular lipolysis of triglyceride rich lipoproteins. Impaired LPL activity leads to the accumulation of chylomicrons and very low-density lipoproteins (VLDL) in plasma, resulting in hypertriglyceridemia. While low-density lipoprotein cholesterol (LDL-C) is recognized as a primary risk factor for atherosclerosis, hypertriglyceridemia has been shown to be an independent risk factor for cardiovascular disease (CVD) and a residual risk factor in atherosclerosis development. In this review, we focus on the lipolysis machinery and discuss the potential role of triglycerides, remnant particles, and lipolysis mediators in the onset and progression of atherosclerotic cardiovascular disease (ASCVD). This review details a number of important factors involved in the maturation and transportation of LPL to the capillaries, where the triglycerides are hydrolyzed, generating remnant lipoproteins. Moreover, LPL and other factors involved in intravascular lipolysis are also reported to impact the clearance of remnant lipoproteins from plasma and promote lipoprotein retention in capillaries. Apolipoproteins (Apo) and angiopoietin-like proteins (ANGPTLs) play a crucial role in regulating LPL activity and recent insights into LPL regulation may elucidate new pharmacological means to address the challenge of hypertriglyceridemia in atherosclerosis development.

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The Angiopoietin-Like Protein 3 and 8 Complex Interacts with Lipoprotein Lipase and Induces LPL Cleavage

Cited by 26 publications

References 28 publications

GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity

GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity

Angiopoietin-Like Protein 3 (ANGPTL3) Modulates Lipoprotein Metabolism and Dyslipidemia

The Importance of Lipoprotein Lipase Regulation in Atherosclerosis

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