Fatty acid synthesis, specific inhibition

Treating mice with 23 led to the inhibition of atherosclerotic progression, whereas macrophage-specific knockout of LXR exacerbates atherosclerosis [111]. In vivo activation of LXR leads to increased fatty acid synthesis, accumulation of TG and the development of hepatic steatosis [109]. Successful LXR agonists will show desirable HDL elevation without these side effects [112]. 

G D Agnolo, IS Rosenfeld, J Awaya, S Omura, PR Vagelos. Inhibition of fatty acid synthesis by the antibiotic cerulenin specific inactivation of P-ketoacyl-acyl carrier protein synthase. Biochem Biophys Acta 236 155-166, 1973. 

There is abundant evidence indicating that a natural hydrophobic inhibitor of acetyl-CoA carboxylase is present in crude enzyme extracts of liver and adipose tissue [128,129,182,192,236-238]. The activating effect of (+)-palmityl carnitine on fatty acid synthesis in crude liver extracts and on impure acetyl-CoA carboxylase preparations has tentatively been ascribed to the displacement of hydrophobic inhibitors such as fatty acids or fatty acyl-CoA derivatives [129,182,192,236-238]. Inhibition of rat liver acetyl-CoA carboxylase by added palmityl-CoA can be reversed in part by (+)-palmityl carnitine [236], but not by citrate. This activating effect does not appear to be specific with respect to (+)-palmityl carnitine in that cetyl trimethylammonium ion is also effective [192]. Furthermore, impure preparations of acetyl-CoA carboxylase from adipose tissue or rat liver are markedly activated by serum albumin [123,129,238] or extensive dilution of the enzyme preparation prior to assay [129,182]. On the other hand, none of these agents [(+)-palmityl carnitine, serum albumin, or dilution], which activate the impure carboxylase, have an activating effect on the homogeneous acetyl-CoA carboxylases from adipose tissue or liver [129,182, 239]. It is evident that an inhibitory substance, apparently hydrophobic in nature, is removed either by purification of the enzyme or by the agents or treatments mentioned above. 

Since the enzyme can be totally inactivated by a stoichiometric amount of this acetylene, a single turnover is all that is required for irreversible inhibition to occur. The enormous specificity of this inhibitor in multi-component systems and in vivo was demonstrated in the classic experiments of Kass and Bloch, 5 These experiments showed that B-hydroxy-decanoyl thloester dehydrase was absolutely required for unsaturated fatty acid synthesis in E. coll. 

DAgnolo G, Rosenfeld IS, Awaya J, Omura S, Vagelos PR. Inhibition of fatty acid synthesis by the antibiotic cerulenin. Specific inactivation of B-ketoacyl-acyl carrier protein synthetase. Biochim Biophys Acta 1973 326 155-166. 

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