The role of intestinal stearoyl-CoA desaturase 1 in intestinal and systemic lipid and energy metabolism
Creators: name: Burchat, Natalie Anne
Publisher: name: No Publisher Supplied
Year: 2023

description: Stearoyl-CoA desaturase 1 (SCD) is an endoplasmic reticulum-residing enzyme that converts saturated fatty acids into monounsaturated fatty acids through the insertion of a double bond at the 9 position. This conversion of saturated fatty acids (SFA) to monounsaturated fatty acids (MUFA) is a key and highly regulated step in lipid metabolism because the MUFA products of SCD1 are the preferred substrates for the synthesis of other lipid species, including triacylglycerols (TAG), cholesterol esters (CE), phospholipids (PL), and diacylglycerols (DAG). Prior studies have shown that disruptions to SCD1 lead to alterations in esterified lipids, protection from diet-induced obesity, increased energy expenditure and improved glucose tolerance. Given the important roles the intestine plays in the digestion, absorption, and secretion of nutrients into the body, and as a regulatory and signaling organ, the specific contributions of intestinal SCD1 to systemic lipid metabolism and energy balance were investigated. SCD1 gene and protein expression was found to be expressed along the length of the intestine, with the greatest expression in the distal small intestine and colon. Intestinal SCD1 is also regulated in a nutritional manner, as seen in mice fasted then refed a high-sucrose diet which upregulates SCD1 in each segment of the intestine, particularly in the distal intestine. Given the spatial and nutritional regulation of intestinal SCD1, we generated intestine-specific knockout (iKO) mice to assess the specific contribution of intestinal SCD1 to whole-body lipid and energy metabolism. This deletion did not have significant impacts on body weights, body composition, intestinal fat absorption or motility. Lipidomic analyses of the intestine revealed that intestinal SCD1 modulates intestinal lipid content particularly TAGs and CEs in the proximal and distal small intestine. Intestinal SCD1 also regulates plasma lipid content and hepatic lipid composition, with notable reductions in the 14:1/14:0 desaturation ratio. This reduction in myristoleate may mediate reductions in hepatic expression of the Pgc1a-Sirt1 axis and fatty acid oxidation. Given prior reports of Scd1 deficient animals being protected from diet-induced obesity due to increased energy expenditure, and our findings that intestinal SCD1 regulates intestinal and systemic lipid metabolism, the role of intestinal SCD1 in systemic energy balance was investigated. iKO mice were maintained on a chow diet or fed a 45% high-fat diet (HFD) for metabolic profiling. Chow fed iKO mice had increased plasma and hepatic bile acid content and decreased fecal bile acid excretion. Notably, expression of apical sodium dependent bile acid transporter (Asbt) was increased in iKO mice, potentially mediating increased ileal uptake of bile acids. This altered bile acid profile was associated with increased expression of Takeda G protein-coupled receptor 5 (TGR5) signaling targets, including Dio2 in brown adipose tissue and plasma glucagon-like peptide 1 (GLP-1). iKO mice on a HFD had reduced metabolic efficiency due to decreased weight gain despite increased food consumption. HFD-fed iKO mice had increased energy expenditure and improved glucose tolerance. Altogether, these studies indicate an important role of intestinal SCD1 on modulating intestinal and whole-body lipid content and composition and suggest a role for intestinal SCD1 in the regulation of bile acid and energy homeostasis.