Alkandari, Mariam; (2022) Natural Product Inhibitors of Acetyl-CoA Carboxylase - A Drug Target in Type 2 Diabetes Mellitus. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The prevalence of Type 2 Diabetes Mellitus (T2DM) is increasing worldwide, creating a significant global health burden. This increase in T2DM cases is mostly attributed to the growing prevalence of obesity, which is associated with an increased release of fatty acids from the enlarged adipose tissue into plasma. Plasma fatty acids are ultimately deposited in non-adipose peripheral tissue, in which they interfere with insulin signalling leading to insulin resistance, a phenomenon known as lipotoxicity. Acetyl-CoA carboxylase (ACC), a key enzyme in fatty acid metabolism, is present in two isoforms, namely ACC1 and ACC2, displaying different tissue distribution and biological functions. The two isoforms are physiologically regulated by the energy-sensing AMP-activated protein kinase (AMPK). The latter is activated in response to low cellular energy, leading to the inhibitory phosphorylation of ACC among other effects. The inhibition of ACC1 reduces fatty acid synthesis in lipogenic tissue such as the adipose tissue and liver, while inhibition of ACC2 stimulates fatty acid oxidation in oxidative tissue such as skeletal muscle and also the liver. Based on the association between impaired lipid metabolism and insulin resistance, ACC may present a target for the treatment of T2DM. Indeed, published evidence demonstrated that the inhibition of ACC1 and/or ACC2 results in reduced triglyceride content in non-adipose tissue, improved insulin sensitivity, and lower blood glucose levels in experimental animal models of T2DM. Various medicinal plants and isolated natural products have shown to be effective in the management of T2DM in in vivo models. In this project, plant extracts, prepared using sequential solvent extraction, were screened against ACC1 in vitro. Following bioactivity guided fractionation of plants showing promising ACC inhibition, carnosic acid, piperine, and gallic acid were identified as ACC inhibitors with IC5O values in the high micromolar range against ACC1 and ACC2. Carnosic acid was also identified as an AMPK activator leading to increased fatty acid oxidation and reduced triglycerides in a human liver cancer cell line (HepG2). Its effect on the AMPK/ACC pathway was evident at concentrations as low as 5 µM as confirmed by western blot analysis of phosphoproteins. Along with reductions in triglyceride content, carnosic acid led to improved insulin mediated AKT signalling, reduced glucose production and increased glycogen synthesis in fatty acid-induced insulin resistant HepG2 cells. When carnosic acid was tested in AMPK knocked down HepG2 cells, its hypolipidemic and antidiabetic effects were abolished, suggesting that they are likely to be mediated via AMPK activation.

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