Inhibition of Insulin and T₃‐Induced Fatty Acid Synthase by Hexanoate

Abstract

Fatty acid synthase (FAS) is responsible for the de novo synthesis of palmitate and stearate. This enzyme is activated by insulin and T(3), and inhibited by fatty acids. In this study, we show that insulin and T(3) have an inducing effect on FAS enzymatic activity, which is synergetic when both hormones are present. Octanoate and hexanoate specifically inhibit this hormonal effect. A similar inhibitory effect is observed at the level of protein expression. Transient transfections in HepG2 cells revealed that hexanoate inhibits, at least in part, FAS at a transcriptional level targeting the T(3) response element (TRE) on the FAS promoter. The effect of C6 on FAS expression cannot be attributed to a modification of insulin receptor activation or to a decrease in T(3) entry in the cells. Using bromo-hexanoate, we determined that hexanoate needs to undergo a transformation in order to have an effect. When incubating cells with triglyceride-hexanoate or carnitine-hexanoate, no effect on the enzymatic activity induced by insulin and T(3) is observed. A similar result was obtained when cells were incubated with betulinic acid, an inhibitor of the diacylglycerol acyltransferase. However, the incubation of cells with Triacsin C, a general inhibitor of acyl-CoA synthetases, completely reversed the inhibitory effect of hexanoate. Our results suggest that in hepatic cells, hexanoate needs to be activated into a CoA derivative in order to inhibit the insulin and T(3)-induced FAS expression. This effect is partially transcriptional, targeting the TRE on the FAS promoter.

Priming by Hexanoic Acid Induce Activation of Mevalonic and Linolenic Pathways and Promotes the Emission of Plant Volatiles

“…It has been suggested that Hx as well as the medium chain fatty acid enter the cell rapidly by simple diffusion without implication of specific transporters. Then, Hx is rapidly transformed into an acyl-CoA derivative through the action of a specific acyl-CoA synthetase ( Akpa et al, 2010 ). As a substrate, the presence of Hx in plants has been extensively studied in Cannabis sativa , where it is transformed into hexanoyl-CoA ( Stout et al, 2012 ).…”

Gut Microbiota and Metabolic Health: The Potential Beneficial Effects of a Medium Chain Triglyceride Diet in Obese Individuals

“…Finally, in the liver, MCFA are preferentially metabolized to generate energy [ 107 ]. In fact, MCFA are known to enter cells passively before crossing mitochondria membranes, independently of the availability of the rate-limiting carnitine palmitoyltransferase 1 (CPT-1) transport system, to fuel the β-oxidation and ATP-generating pathways [ 105 , 106 ], induce thermogenesis and reduce de novo lipogenesis [ 108 ].…”

“…Using chick embryo hepatocytes, we have previously demonstrated, that free non-esterified hexanoate and octanoate significantly decrease insulin and T3 (triiodothyronine)-induced fatty acid synthase (FAS) expression and activity [ 108 ]. Activity of FAS, a key enzyme of de novo lipogenesis, is positively regulated in the post-prandial state by several hormones (such as insulin, ghrelin and T3) and nutrients (dietary lipid and carbohydrate derivatives) [ 109 , 110 ], and is an important contributor to obesity and NAFLD [ 20 , 111 ].…”

Metabolically Healthy Obesity

“…MCTs are also used in preterm infant formulas [106] [109,110], and is an important contributor to obesity and NAFLD [20,111]. We and others have demonstrated that MCFA inhibit binding of transactivating receptors on the T3 response elements of FAS and Acetyl-CoA carboxylase (ACC) promoters [108,[112][113][114]. Using LO2 hepatocytes, Wang and collaborators showed that the induction of cellular steatosis by LCT (esterified oleate and palmitate) is reversed by addition of either octanoate or decanoate.…”