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

Abstract

Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation and may favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver disease. Using structure-based drug design, we have identified a series of potent allosteric protein–protein interaction inhibitors, exemplified by ND-630, that interact within the ACC phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit the enzymatic activity of both ACC isozymes, reduce fatty acid synthesis and stimulate fatty acid oxidation in cultured cells and in animals, and exhibit favorable drug-like properties. When administered chronically to rats with diet-induced obesity, ND-630 reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to Zucker diabetic fatty rats, ND-630 reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c (0.9% reduction). Together, these data suggest that ACC inhibition by representatives of this series may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease.

Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

“…A further limitation is the difficulty in discerning which cell type or organ system is playing the most prominent role in mediating the beneficial effects of salsalate. Inhibition of hepatic DNL has shown therapeutic promise for NAFLD (72), as has promoting hepatic substrate consumption (62), indicating that the liver may be important. However, increasing BAT mitochondrial activity has been shown to spare the liver from substrate oversupply (46), and skeletal muscle is responsible for the majority of glucose clearance (73).…”

Analysis of Arabidopsis Accessions Hypersensitive to a Loss of Chloroplast Translation

“…Human ACCase is controlled by allosteric regulation, protein-protein interactions, reversible phosphorylation, and oligomerization (Brownsey et al, 2006;Tong, 2013). Chemical inhibitors have been developed that interfere with dimerization of one or both isoforms, modify fatty acid metabolism, and represent promising treatments for diabetes, obesity, and other human diseases (Marjanovic et al, 2010;Harriman et al, 2016).…”

“…This work provides valuable insights into essential domains within a large, homodimeric enzyme that represents a target for herbicide action (Kaundun, 2014) and pharmaceuticals for human diseases (Harriman et al, 2016). Identification of Arabidopsis accessions hypersensitive to spectinomycin should also advance research on chloroplast transformation, where spectinomycin is the selection agent of choice (Svab and Maliga, 1993), and may help to uncover a novel function for ACC2 in some Arabidopsis populations.…”

Global mRNA and Long Non-Coding RNA Expression in the Placenta and White Adipose Tissue of Mice Fed a High-Fat Diet During Pregnancy

“…Combined with the result obtained for placenta, we speculated that some hormones or cell factors secreted from the placenta might suppress energy metabolism, nutrient uptake, and insulin sensitivity in adipose tissue, promote placental development and supply more glucose to foetal growth. The results obtained for the placenta showed that one of the serpin peptides, serpina3n, was significantly increased in HFD mice [33][34][35]. Serpina3n was abnormally highly increased in a Long-Evans agouti T2DM rat model and T2DM patient serum and positively associated with the level of insulin in serum [36], indicating that it might play an important role in energy metabolism and nutrient synthesis in gonadal tissue.…”