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Intestinal Lipoprotein Overproduction, a Newly Recognized Component of Insulin Resistance, Is Ameliorated by the Insulin Sensitizer Rosiglitazone: Studies in the Fructose-Fed Syrian Golden Hamster

Departments of Medicine and Physiology (G.F.L., K.U., L.S.), Division of Endocrinology and Metabolism, and the Department of Laboratory Medicine and Pathobiology (M.N., M.H., K.A.), Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 2C4

Address all correspondence and requests for reprints to: Gary F. Lewis, Toronto General Hospital, 200 Elizabeth Street, EN11-229, Toronto, Ontario, Canada M5G 2C4. E-mail: gary.lewis{at}uhn.on.ca.

We investigated whether intestinal lipoprotein overproduction in a fructose-fed, insulin-resistant hamster model is prevented with insulin sensitization. Syrian Golden hamsters were fed either chow, 60% fructose for 5 wk, chow for 5 wk with the insulin sensitizer rosiglitazone added for the last 3 wk, or 60% fructose plus rosiglitazone. In vivo Triton studies showed a 2- to 3-fold increase in the large (Svedberg unit > 400) and smaller (S_f 100–400) triglyceride-rich lipoprotein particle apolipoprotein B48 (apoB48) but not triglyceride secretion with fructose feeding in the fasted state (P < 0.01) and partial normalization with rosiglitazone in fructose-fed hamsters. Ex vivo pulse-chase labeling of enterocytes confirmed the oversecretion of apoB48 lipoproteins with fructose feeding. Intestinal lipoprotein oversecretion was associated with increased expression of microsomal triglyceride transfer protein expression. With rosiglitazone treatment of fructose-fed hamsters, there was approximately 50% reduction in apoB48 secretion from primary cultured enterocytes and amelioration of the elevated microsomal triglyceride transfer protein mass and activity in fructose-fed hamsters. In contrast, in the postprandial state, the major differences between nutritional and drug intervention protocols were evident in triglyceride-rich lipoprotein triglyceride and not apoB48 secretion rates. The data suggest that intestinal lipoprotein overproduction can be ameliorated with the insulin sensitizer rosiglitazone.

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