Acute Regulation of Postprandial Lipemia and Chylomicron Production by Glucagon-Like Peptide-1 and Bile Acid Signaling

Postprandial dyslipidemia is a key feature of insulin resistance that involves the overproduction of chylomicron particles from the intestine after a meal, resulting in an excess number of atherogenic lipoprotein remnants. A number of factors are released postprandially that regulate energy homeostasis including gut peptides that signal to the brain and bile acids that act on intestinal receptors. In particular, the anti-diabetic hormone glucagon-like peptide-1 (GLP-1) has received attention as both a gut peptide and CNS neuropeptide. Here I examined the utility of targeting central glucagon-like peptide-1 receptors (GLP-1R) or peripheral bile acid receptors for lowering postprandial lipemia and chylomicron production. The Syrian Golden hamster model was used to study chylomicron secretion, while C57BL/6 mice were employed to examine bile acid profiles and signaling. Injecting the GLP-1R agonist exendin-4 directly into the third ventricle of the brain significantly decreased plasma triglyceride levels as well as the number of chylomicron particles secreted after an oral fat load. These effects were prevented by inhibiting central melanocortin-4 receptors or sympathetic neurotransmission, demonstrating the pharmacological activation of a brain-gut axis. Bile acids were similarly examined as postprandial factors that regulate lipid digestion and lipoprotein release. Intraduodenal bile acid administration decreased plasma triglyceride levels, in part by slowing gastric emptying. Specific targeting of the nuclear farnesoid X receptor (FXR) lowered circulating and intestinal triglyceride levels and increased intestinal markers of fatty acid oxidation. Finally, a potential interplay between GLP-1 and bile acid signaling was observed in exendin-4-treated mice, which displayed altered expression of protein kinase C isoforms (FXR activators) in the gut and upregulation of the rate limiting enzyme for bile acid synthesis in the liver. Altogether, the findings arising from these studies support the potential utility of targeting central GLP-1 and peripheral bile acid receptors in the treatment of postprandial lipoprotein overproduction.Ph.D.2018-12-19 00:00:0