Multi-organ Coordination of Lipoprotein Secretion by Hormones, Nutrients and Neural Networks

Abstract

Plasma triglyceride-rich lipoproteins (TRL), particularly atherogenic remnant lipoproteins, contribute to atherosclerotic cardiovascular disease. Hypertriglyceridemia may arise in part from hypersecretion of TRLs by the liver and intestine. Here we focus on the complex network of hormonal, nutritional, and neuronal interorgan communication that regulates secretion of TRLs and provide our perspective on the relative importance of these factors. Hormones and peptides originating from the pancreas (insulin, glucagon), gut [glucagon-like peptide 1 (GLP-1) and 2 (GLP-2), ghrelin, cholecystokinin (CCK), peptide YY], adipose tissue (leptin, adiponectin) and brain (GLP-1) modulate TRL secretion by receptor-mediated responses and indirectly via neural networks. In addition, the gut microbiome and bile acids influence lipoprotein secretion in humans and animal models. Several nutritional factors modulate hepatic lipoprotein secretion through effects on the central nervous system. Vagal afferent signaling from the gut to the brain and efferent signals from the brain to the liver and gut are modulated by hormonal and nutritional factors to influence TRL secretion. Some of these factors have been extensively studied and shown to have robust regulatory effects whereas others are "emerging" regulators, whose significance remains to be determined. The quantitative importance of these factors relative to one another and relative to the key regulatory role of lipid availability remains largely unknown. Our understanding of the complex interorgan regulation of TRL secretion is rapidly evolving to appreciate the extensive hormonal, nutritional, and neural signals emanating not only from gut and liver but also from the brain, pancreas, and adipose tissue.

Keywords: adipose; brain; chylomicrons; gut peptides; pancreas; very-low density lipoproteins.

Graphical Abstract

Figure 1.

Mechanisms of lipoprotein secretion and acute regulation by insulin and glucagon. Pancreatic insulin acutely suppresses chylomicron (CM) and very low density lipoprotein (VLDL) secretion via several mechanisms in enterocytes and hepatocytes (green arrows), respectively. In hepatocytes, triglyceride (TG) arises in part from de novo lipogenesis (DNL) to yield free fatty acids (FFA) and intracellular TG storage pools. VLDL particles are formed by progressive lipidation of apolipoprotein B (apoB) by microsomal triglyceride transfer protein (MTP). In enterocytes, TG synthesis in the leaflets of the endoplasmic reticulum (ER) arises from re-esterification of monoacylglycerol (MAG) and diacylglycerol (DAG) by respective transferases (MGAT, DGAT). Cholesterol esters (CE) are incorporated in pre-CMs after absorption via Niemann-Pick C1-Like-1 (NPC1L1). Pre-CMs exit the ER in pre-CM transport vesicles (PCTV) for maturation at the Golgi apparatus prior to secretion as CM. Insulin acutely increases hepatic apoB mRNA p-body formation, decreases MTP-mediated apoB lipidation and MTP expression, and increases postendoplasmic reticulum autophagy. Insulin indirectly alters VLDL-TG production by inhibiting fatty acid (FA) release by adipose tissue. Insulin acutely suppresses CM secretion with decreased apoB48 stability. Some evidence suggests a possible role for the brain in insulin-mediated suppression of VLDL secretion; however, this requires further substantiation. Pancreatic glucagon acutely suppresses VLDL secretion through increased catabolism of FA by beta-oxidation pathways (blue arrow), including increased expression and activity of key beta-oxidation enzymes carnitine acyl transferase -1 and -2 (CPT-1, CPT-2) (12,13).

Figure 2.

Effects of glucagon-like peptide (GLP)-1 and -2 on very-low density lipoprotein (VLDL) and chylomicron (CM) secretion. GLP-1 elicits numerous effects on various tissues to decrease VLDL and CM secretion. GLP-1 enhances glucose-stimulated insulin secretion from the pancreas and delays gastric emptying. In the intestine, GLP-1 decreases gut motility and flow of fluid through the mesenteric lymph ducts. In CM-secreting enterocytes, GLP-1 decreases expression of key CM synthesis proteins including diacylglycerol transferase-1 (DGAT1), microsomal triglyceride transfer protein (MTP) and apolipoprotein B48 (apoB48). Long-term GLP-1 administration increases weight loss and improves glycemic control and insulin sensitivity. Together these effects inhibit CM synthesis and secretion. GLP-1 also decreases hepatic VLDL production, in part by suppressing de novo lipogenesis (DNL) and decreasing triglyceride (TG) content. The gut peptide GLP-2 increases CM secretion in humans and animal models, with robust stimulation of lymph flow in the mesenteric lymphatics. Adapted from “American Diabetes Association, Gut Peptides Are Novel Regulators of Intestinal Lipoprotein Secretion: Experimental and Pharmacological Manipulation of Lipoprotein Metabolism doi: 10.2337/db14-1706, American Diabetes Association, 2015. Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association.