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Atypical angiopoietin-like protein that regulates ANGPTL3

Quagliarini, Fabiana, Wang, Yan, Kozlitina, Julia, Grishin, Nick V., Hyde, Rhonda, Boerwinkle, Eric, Valenzuela, David M., Murphy, Andrew J., Cohen, Jonathan C., Hobbs, Helen H.·2012·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1217552109
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Abstract

Angiopoietin-like proteins (ANGPTLs) play major roles in the trafficking and metabolism of lipids. Inactivation of ANGPTL3 , a gene located in an intron of DOCK7 , results in very low levels of LDL-cholesterol (C), HDL-C and triglyceride (TAG). We identified another ANGPTL family member, ANGPTL8 , which is located in the corresponding intron of DOCK6 . A variant in this family member (rs2278426, R59W) was associated with lower plasma LDL-C and HDL-C levels in three populations. ANGPTL8 is expressed in liver and adipose tissue, and circulates in plasma of humans. Expression of ANGPTL8 was reduced by fasting and increased by refeeding in both mice and humans. To examine the functional relationship between the two ANGPTL family members, we expressed ANGPTL3 at physiological levels alone or together with ANGPTL8 in livers of mice. Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3. ANGPTL8 coimmunoprecipitated with the N-terminal domain of ANGPTL3 in plasma of these mice. In cultured hepatocytes, ANGPTL8 expression increased the appearance of N-terminal ANGPTL3 in the medium, suggesting ANGPTL8 may activate ANGPTL3. Consistent with this scenario, expression of ANGPTL8 in Angptl3 −/− mice failed to promote hypertriglyceridemia. Thus, ANGPTL8 , a paralog of ANGPTL3 that arose through duplication of an ancestral DOCK gene, regulates postprandial TAG and fatty acid metabolism by controlling activation of its progenitor, and perhaps other ANGPTLs. Inhibition of ANGPTL8 provides a new therapeutic strategy for reducing plasma lipoprotein levels.

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Crossref · 10.1073/pnas.1217552109

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  • More recent studies have shown that ANGPTL3 forms a complex with ANGPTL8 and that this complex is most likely the physiologically relevant LPL inhibitor.

    “As discussed below, more recent studies have shown that ANGPTL3 forms of complex with ANGPTL8 and that this complex is most likely the physiologically relevant LPL inhibitor (19, 54, 115, 137, 138).”

    From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [19]

    The Discussion reports that ANGPTL3 and ANGPTL8 physically interact and coimmunoprecipitate, supporting the complex portion of the claim. It does not establish that their complex is the physiologically relevant LPL inhibitor: the Discussion treats a functional complex as one possible mechanism, and the A B section reports no significant decrease in plasma lipolytic activity after ANGPTL8 overexpression. (LLM, conf=0.87)

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  • ANGPTL8 is expressed primarily in the adipose tissue and liver of mice, and its expression is much higher in the fed state than in the fasted state.

    “All three studies also found that ANGPTL8 is expressed primarily in the adipose tissue and liver of mice and that expression was much higher in the fed state than in the fasted state.”

    From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [19]

  • Overexpression of ANGPTL8 in the absence of ANGPTL3, or vice versa, has limited ability to increase plasma triglycerides.

    “overexpression of ANGPTL8 in the absence of ANGPTL3, or vice versa, has limited ability to increase plasma triglycerides (19, 115, 137)”

    From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [19]

  • ANGPTL8 is expressed in adipose tissue where ANGPTL3 is not expressed.

    “Both ANGPTL8 and ANGPTL3 are expressed in the liver, but ANGPTL8 is also expressed in adipose tissue where ANGPTL3 is not expressed (15, 19, 35, 40, 72, 103, 139)”

    From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [19]

  • ANGPTL8 overexpression only increases plasma triglyceride levels if ANGPTL3 is present.

    “ANGPTL8 overexpression only increases plasma triglyceride levels if ANGPTL3 is present (19, 137).”

    From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [19]

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Citations

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Research works printed but not linked: 32

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Metadata

Authors
Quagliarini, F., Wang, Y., Kozlitina, J., Grishin, N. V., Hyde, R., Boerwinkle, E., Valenzuela, D. M., Murphy, A. J., Cohen, J. C., & Hobbs, H. H.
Affiliations
  • Department of Internal Medicine,
  • Department of Biophysics, and
  • Division of Epidemiology School of Public Health, University of Texas, Houston, TX 77030; and
  • Regeneron Pharmaceuticals, Tarrytown, NY 10591
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2012-11-12
Volume
109
Issue
48
Pages
19751-19756
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.1217552109
Cited by
409
References
4
Language
en

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