Abstract 1949 Stearoyl-CoA desaturase-1 deficiency increases hepatic and plasma levels of Saturated Long-Chain Acylcarnitines under a high carbohydrate feeding

Stearoyl-CoA desaturase (SCD) synthesizes monounsaturated fatty acids (MUFA) from saturated fatty acids by introducing a single, double bond in a range of methylene-interrupted fatty acyl-CoA substrates; and preferentially catalyzes the desaturation of palmitoyl- and stearoyl-CoA to palmitoleoyl- and oleoyl-CoA, respectively. High levels of SCD1 and their MUFA products are associated with obesity, diabetes, and fatty liver. Indeed, global, and liver-specific deletion of SCD1 improved insulin sensitivity and protected them against obesity and fatty liver. Although our previous studies showed that SCD1 deficiency altered liver fat content, the effect of SCD1 ablation on acylcarnitines is not yet established. All studies involving animals were conducted according to the guidelines of the Institutional Animal Care and Use Committee of The University of Wisconsin-Madison. Our findings show that under a high carbohydrate low-fat diet, global and liver-specific SCD1 deficiency downregulated the hepatic expression of genes related to acylcarnitine metabolism, including Carnitine Palmitoyltransferase 1 (Cpt1), Cpt2, and hepatocyte nuclear factor 4 alpha (HNF4α), a known regulator of Cpt1 and Cpt2. Lipidomic analysis revealed a 5- and 12-fold increase in 16:0 acyl- and 18:0 acyl-carnitines, respectively, in the liver, and a 5- and 49-fold increase in 16:0 acyl- and 18:0 acyl-carnitines, respectively, in the plasma in the global SCD1 deficient mice. To investigate whether these changes are liver-specific we performed targeted lipidomics in SCD1 liver-specific knockout (LKO) mice. Our findings in the LKO mice also revealed an increase in hepatic carnitine and a concomitant increase in short-chain and long-chain acylcarnitines both in the liver and plasma. Despite the increased acylcarnitines that have been implicated in several metabolic stresses, such as insulin resistance, the SCD1-deficient mice exhibited improved insulin sensitivity and were protected against diet-induced obesity and fatty liver. These findings suggest that acylcarnitine accumulation per se may not result in insulin resistance, suggesting a role for downstream fatty acid catabolism beyond acylcarnitine formation. Funded by NIH.