title: New and emerging regulators of intestinal lipoprotein secretion.
abstract: Overproduction of hepatic apoB100-containing VLDL particles has been well documented in animal models and in humans with insulin resistance such as the metabolic syndrome and type 2 diabetes, and contributes to the typical dyslipidemia of these conditions. In addition, postprandial hyperlipidemia and elevated plasma concentrations of intestinal apoB48-containing chylomicron and chylomicron remnant particles have been demonstrated in insulin resistant states. Intestinal lipoprotein production is primarily determined by the amount of fat ingested and absorbed. Until approximately 10 years ago, however, relatively little attention was paid to the role of the intestine itself in regulating the production of triglyceride-rich lipoproteins (TRL) and its dysregulation in pathological states such as insulin resistance. We and others have shown that insulin resistant animal models and humans are characterized by overproduction of intestinal apoB48-containing lipoproteins. Whereas various factors are known to regulate hepatic lipoprotein particle production, less is known about factors that regulate the production of intestinal lipoprotein particles. Monosacharides, plasma free fatty acids (FFA), resveratrol, intestinal peptides (e.g. GLP-1 and GLP-2), and pancreatic hormones (e.g. insulin) have recently been shown to be important regulators of intestinal lipoprotein secretion. Available evidence in humans and animal models strongly supports the concept that the small intestine is not merely an absorptive organ but rather plays an active role in regulating the rate of production of chylomicrons in fed and fasting states. Metabolic signals in insulin resistance and type 2 diabetes and in some cases an aberrant intestinal response to these factors contribute to the enhanced formation and secretion of TRL. Understanding the regulation of intestinal lipoprotein production is imperative for the development of new therapeutic strategies for the prevention and treatment of dyslipidemia. Here we review recent developments in this field and present evidence that intestinal lipoprotein production is a process with metabolic plasticity and that modulation of intestinal lipoprotein secretion may be a feasible therapeutic strategy in the treatment of dyslipidemia and possibly prevention of atherosclerosis.
authors.affiliation: Department of Medicine, University of Toronto, Canada; Department of Physiology, University of Toronto, Canada; Banting and Best Diabetes Centre, Toronto General Hospital, 200 Elizabeth Street, EN12-218, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Changting
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Department of Medicine, University of Toronto, Canada; Department of Physiology, University of Toronto, Canada; Banting and Best Diabetes Centre, Toronto General Hospital, 200 Elizabeth Street, EN12-218, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Satya
authors.initials: S
authors.lastname: Dash
authors.affiliation: Department of Medicine, University of Toronto, Canada; Department of Physiology, University of Toronto, Canada; Banting and Best Diabetes Centre, Toronto General Hospital, 200 Elizabeth Street, EN12-218, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Morgantini
authors.affiliation: Department of Medicine, University of Toronto, Canada; Department of Physiology, University of Toronto, Canada; Banting and Best Diabetes Centre, Toronto General Hospital, 200 Elizabeth Street, EN12-218, Toronto, Ontario M5G 2C4, Canada. Electronic address: gary.lewis@uhn.ca.
authors.forename: Gary F
authors.initials: GF
authors.lastname: Lewis
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100 / Q000502:physiology; D053283:Apolipoprotein B-48 / Q000502:physiology; D050197:Atherosclerosis / Q000209:etiology / Q000517:prevention & control; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D002914:Chylomicrons / Q000378:metabolism; D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000503:physiopathology; D004040:Dietary Carbohydrates / Q000494:pharmacology; D004041:Dietary Fats / Q000494:pharmacology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D050171:Dyslipidemias / Q000209:etiology / Q000503:physiopathology*; D000077270:Exenatide; D005230:Fatty Acids, Nonesterified / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000502:physiology; D053767:Glucagon-Like Peptide 2 / Q000502:physiology; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D054795:Incretins / Q000502:physiology; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D007421:Intestine, Small / Q000378:metabolism* / Q000382:microbiology; D008074:Lipoproteins / Q000378:metabolism*; D064307:Microbiota; D010455:Peptides / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors; D000077185:Resveratrol; D012636:Secretory Rate; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood; D014688:Venoms / Q000494:pharmacology
chemical_list: D053299:Apolipoprotein B-100; D053283:Apolipoprotein B-48; D001647:Bile Acids and Salts; D002914:Chylomicrons; D004040:Dietary Carbohydrates; D004041:Dietary Fats; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005230:Fatty Acids, Nonesterified; C000593833:GLP1R protein, human; D053767:Glucagon-Like Peptide 2; D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins; D007328:Insulin; D008074:Lipoproteins; D010455:Peptides; D018027:Receptors, Glucagon; D013267:Stilbenes; D014280:Triglycerides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D002784:Cholesterol; D000077270:Exenatide; D000077185:Resveratrol
keywords: Chylomicron; GLP-1; GLP-2; Intestine; Lipoprotein; Resveratrol