The intestine is emerging as a regulatory and signaling organ, enabling diet-derived nutrients to perform essential actions. A better understanding of intestinal regulation of systemic lipid metabolism has direct implications to multiple human metabolic pathologies, including cardiovascular disease, fatty liver, and insulin resistance. The delta-9 desaturase, stearoyl-CoA desaturase-1 (SCD1), converts saturated fatty acids to monounsaturated products and has been shown to regulate lipid esterification in liver and skin. However, virtually nothing is known about the role of SCD1 in the intestine, where lipid esterification is crucial for its eventual absorption and secretion into chylomicrons (CMs). To address this gap in knowledge, we generated mice with a targeted deletion of SCD1 only in intestinal epithelial cells (iKO mice). Remarkably, we find that iKO animals have significant reductions not only in intestinal lipids, but also in circulating and hepatic lipid levels, particularly in levels of monounsaturated fatty acids. iKO mice also have significant increases in both energy expenditure and glucose tolerance, accompanied by increased thermogenic markers in brown adipose tissue and increased plasma GLP-1 levels. Unexpectedly, intestinal SCD1 deletion elevates plasma and hepatic bile acids (BAs) and alters markers of hepatobiliary BA efflux and ileal BA reuptake. Supported by these and other compelling preliminary data, this application will assess the role of intestinal SCD1 in integrating metabolic signals originating in the gut. The central hypothesis of this application is that intestinal SCD1 regulates metabolic health by altering secreted lipid content and composition, TGR5 signaling in BAT and the gut, and enterohepatic BA metabolism. This hypothesis will be tested by our two related but independent Specific Aims. In Aim 1, we will test the relevance of intestinal SCD1 inhibition to energy balance in the context of hypercaloric and hyperlipidemic diets. We will also evaluate a mechanistic role for TGR5 in mediating the improved metabolic phenotypes of iKO mice. In Aim 2, we will evaluate a role for SCD1-derived MUFAs in regulating hepatic BA efflux and intestinal BA reuptake . We will also utilize a) an inhibitor of intestinal BA reuptake, b) a gut-restricted FXR agonist, and c) dietary MUFAs to restore hepatic and plasma BA levels in iKO mice.
|Effective start/end date||7/1/21 → 5/31/22|
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