Role of Intestinal Stearoyl‐CoA Desaturase 1 in Whole‐Body Lipid Metabolism and Metabolic Health

Abstract

Stearoyl‐CoA desaturase 1 (SCD1) is an ER‐resident enzyme that converts saturated fatty acids into monounsaturated fatty acids (MUFAs). These MUFAs are the preferred substrates for the synthesis of lipid species such as cholesterol esters and triglycerides. The intestine plays an important role in both lipid absorption and assimilation. Cholesterol and free fatty acids must be esterified into cholesterol esters (CE) and triglycerides (TG), respectively, for efficient secretion of chylomicrons for eventual lipid assimilation. Given the important role of SCD1 in modulating the esterification of both CE and TG, we hypothesized that intestinal SCD1 may regulate lipid secretion from the intestine. Our studies show that SCD1 protein and gene increases along the length of the intestine and this expression is induced by fasting followed by refeeding a high sucrose very low‐fat diet. To study the role of intestinal SCD1 in lipid metabolism, intestine‐specific knockout (iKO) mice were generated by crossing SCD1 floxed mice with mice expressing Cre recombinase under the control of the villin promoter. Our studies reveal that these mice have a 13% reduction in steady‐state plasma lipids, with a specific reduction in plasma triglycerides and free cholesterol. They also have reduced hepatic diacylglycerols and cholesterol esters, with a particular reduction in species containing the MUFA myristoleic acid (14:1). iKO mice have altered lipid composition in the distal intestine, where SCD1 is more highly expressed and regulated. In addition to these alterations in lipid handling, iKO mice have increases in plasma and hepatic bile acids, potentially due to an inability to efficiently esterify cholesterol. Downstream signaling via bile acids is elevated in iKO mice, resulting in activation of TGR5 signaling in brown adipose tissue and the ileum. Thus, our results indicate that deletion of intestinal SCD1 has significant impacts on whole‐body energy balance and lipid metabolism.