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Cited by 287Cancer, Lipids, and MetabolismLiver Disease Diagnosis and TreatmentPeroxisome Proliferator-Activated Receptors

Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats

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Harriman, Geraldine, Greenwood, Jeremy, Bhat, Sathesh, Huang, Xinyi, Wang, Ruiying, Paul, Debamita, Tong, Liang, Saha, Asish K. +3 more·2016·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1520686113PMC PMC4822632
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Abstract

Significance: Using structure-based drug design, we have identified a series of potent allosteric protein–protein interaction acetyl-CoA carboxylase inhibitors, exemplified by ND-630, that interact within the acetyl-CoA carboxylase subunit phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit enzymatic activity. ND-630 reduces fatty acid synthesis and stimulates fatty acid oxidation in cultured cells and experimental animals, reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia in diet-induced obese rats and reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c in Zucker diabetic fatty rats. These data suggest that ND-630 may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes, and fatty liver disease.

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  • Both de novo FA synthesis and lipolysis contribute to neuronal LD formation.

    “ACC inhibition by ND-630 (Harriman et al., 2016) or cPLA2 by MAFP (Longo et al., 1999) for 24 h reduced LD volume in both E3 and E4 neurons (Figure 1H), indicating both de novo FA synthesis and lipolysis contributed to LD formation.”

    From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Harriman et al., 2016

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Authors
Harriman, G., Greenwood, J., Bhat, S., Huang, X., Wang, R., Paul, D., Tong, L., Saha, A. K., Westlin, W. F., Kapeller, R., & Harwood, H. J.
Affiliations
  • Nimbus Therapeutics, Cambridge, MA 02141;
  • Schrodinger (United States) (US)
  • Pharmaron (China) (CN)
  • Columbia University (US)
  • Boston University (US)
Corresponding author
Harwood, H. James
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2016-03-14
Volume
113
Issue
13
Pages
E1796-805
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1520686113
PMC
PMC4822632
OpenAlex
W2298914518
Cited by
287
References
6
Citations by year
2026: 24 · 2025: 20 · 2024: 21 · 2023: 35 · 2022: 26 · 2021: 28 · 2020: 40 · 2019: 33 · 2018: 30 · 2017: 21 · 2016: 9
FWCI
10.77
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (1s10od012018-01a1)
  • National Institute of General Medical Sciences (P41GM111244)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK067238)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords
acetyl-CoA carboxylase inhibition, acetyl-CoA carboxylase 1, acetyl-CoA carboxylase 2, hepatic steatosis, insulin sensitivity, dyslipidemia, diet-induced obesity, fatty acid synthesis, fatty acid oxidation, allosteric inhibitors, protein-protein interaction inhibitors, glucose-stimulated insulin secretion, type 2 diabetes, metabolic syndrome, structure-based drug design
MeSH terms
Acetyl-CoA Carboxylase, Animals, Enzyme Inhibitors, Fatty Liver, Female, Humans, Insulin Resistance, Male, Obesity, Pyrimidinones, Rats, Zucker, Structure-Activity Relationship, Thiophenes, Rats, Sprague-Dawley, Dyslipidemias, Protein Multimerization, Hep G2 Cells, Molecular Docking Simulation

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