Structure-activity and in vivo evaluation of a novel lipoprotein lipase (LPL) activator

https://doi.org/10.1016/j.bmcl.2016.11.053Get rights and content

Abstract

Elevated triglycerides (TG) contribute towards increased risk for cardiovascular disease. Lipoprotein lipase (LPL) is an enzyme that is responsible for the metabolism of core triglycerides of very-low density lipoproteins (VLDL) and chylomicrons in the vasculature. In this study, we explored the structure-activity relationships of our lead compound (C10d) that we have previously identified as an LPL agonist. We found that the cyclopropyl moiety of C10d is not absolutely necessary for LPL activity. Several substitutions were found to result in loss of LPL activity. The compound C10d was also tested in vivo for its lipid lowering activity. Mice were fed a high-fat diet (HFD) for four months, and treated for one week at 10 mg/kg. At this dose, C10d exhibited in vivo biological activity as indicated by lower TG and cholesterol levels as well as reduced body fat content as determined by ECHO-MRI. Furthermore, C10d also reduced the HFD induced fat accumulation in the liver. Our study has provided insights into the structural and functional characteristics of this novel LPL activator.

Section snippets

Acknowledgements

We wish to thank The Goodyear Corporation, Akron OH for donation of the NMR instrument used in this work. The project described was supported by the National Institute of General Medical Sciences, U54GM104942. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

References (13)

There are more references available in the full text version of this article.

Cited by (13)

  • A triple combination strategy of UHPLC-MS<sup>n</sup>, hypolipidemic activity and transcriptome sequencing to unveil the hypolipidemic mechanism of Nelumbo nucifera alkaloids

    2022, Journal of Ethnopharmacology
    Citation Excerpt :

    Lipoprotein lipase (LPL) played a key role in glucose and lipid metabolism, which had been further proved as a crucial regulatory protein to firmly regulate the plasma TG metabolism. It could catabolize lipoproteins accumulated by TG such as very-low density lipoproteins (VLDL) and chylomicrons (Geldenhuys et al., 2017). According to the results of transcriptome sequencing analysis, the expression of gene ANGPTL4, an inhibitor of LPL, was reduced after being affected by O-nornuciferine (Lichtenstein et al., 2007; Sukonina et al., 2006).

  • Studies on the lipid-regulating mechanism of alisol-based compounds on lipoprotein lipase

    2018, Bioorganic Chemistry
    Citation Excerpt :

    LPL, a 60 ku glycoprotein, consists of 448 amino acid residues. Its secondary structure has not yet been elucidated and may contain two domains: the N-terminal domain (NTD) and the smaller C-terminal domain (CTD) [26]. There is a near-spherical domain at the N-terminus (1–312 residues), consisting of a beta-linked structure, which regulates the binding of LPL to the substrate.

  • Triglyceride-Rich Lipoproteins

    2018, Cardiology Clinics
    Citation Excerpt :

    All compounds increase LPL activity but by different mechanisms. NO-1886 primarily increases adipose LPL messenger RNA levels, whereas C10d directly affects the hydrolytic activity and 50F10 stabilizes the active homodimer structure of LPL.50 All have been tested in rodent models and decrease elevated TG; however, clinical development of NO-1886 was terminated because of side effects.

View all citing articles on Scopus
View full text