Postprandial dyslipidemia in insulin resistance: mechanisms and role of intestinal insulin sensitivity.
Insulin resistance is strongly associated with metabolic dyslipidemia, which is largely a postprandial phenomenon. Though previously regarded as a consequence of delayed triglyceride-rich lipoprotein clearance, emerging evidence present intestinal overproduction of apoB-48-containing lipoproteins as a major contributor to postprandial dyslipidemia. The majority of mechanistic information is however derived from animal models, namely the fructose-fed Syrian Golden hamster, and extension to human studies to date has been limited. Work in our laboratory has established that aberrant insulin signalling exists in the enterocyte, and that inflammation appears to induce intestinal insulin resistance. The intestine is a major site of lipid synthesis in the body, and upregulated intestinal de novo lipogenesis and cholesterogenesis have been noted in insulin resistant and diabetic states. There is also enhanced dietary lipid absorption attributable to changes in ABCG5/8, NPC1L1, CD36/FAT, and FATP4. Proteins that are involved in chylomicron assembly and secretion, including MTP, MGAT, DGAT, apoAI-V, and Sar1 GTPase, show evidence of increased expression and activity levels. Increased circulating free fatty acids, typically observed in insulin resistant states, may serve to deliver lipid substrates to the intestine for enhanced chylomicron assembly and secretion. To compound the dysregulation of intestinal lipid metabolism, there are changes in the secretion of gut-derived peptides, which include GLP-1, GLP-2, and GIP. Thus, accumulating evidence presents intestinal lipoprotein secretion as a highly regulated process that is sensitive to perturbations in whole body energy homeostasis, and is severely perturbed in insulin resistant states.
Hsieh
Joanne
J
Molecular Structure & Function, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, M5G 1X8 Canada.
Hayashi
Amanda A
AA
Webb
Jennifer
J
Adeli
Khosrow
K
D000818:Animals; D002914:Chylomicrons / Q000378:metabolism; D050171:Dyslipidemias / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D019518:Postprandial Period / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D002914:Chylomicrons; D007328:Insulin