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J. Biol. Chem., Vol. 280, Issue 18, 17626-17633, May 6, 2005

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Proteomic Profiling of Hepatic Endoplasmic Reticulum-associated Proteins in an Animal Model of Insulin Resistance and Metabolic Dyslipidemia^*

Jean-Paul F. Morand, Joseph Macri¶, and Khosrow Adeli||

From the Divisions of Clinical Biochemistry, and Structural Biology and Biochemistry, Department of Pediatric Laboratory Medicine, Research Institute, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario M5G 1X8 and the ^¶Department of Laboratory Medicine, Hamilton Regional Laboratory Medicine Program and McMaster University, Hamilton, Ontario L8L 2X2, Canada

Hepatic insulin resistance and lipoprotein overproduction are common features of the metabolic syndrome and insulin-resistant states. A fructose-fed, insulin-resistant hamster model was recently developed to investigate mechanisms linking the development of hepatic insulin resistance and overproduction of atherogenic lipoproteins. Here we report a systematic analysis of protein expression profiles in the endoplasmic reticulum (ER) fractions isolated from livers of fructose-fed hamsters with the intention of identifying new candidate proteins involved in hepatic complications of insulin resistance and lipoprotein dysregulation. We have profiled hepatic ER-associated proteins from chow-fed (control) and fructose-fed (insulin-resistant) hamsters using two-dimensional gel electrophoresis and mass spectrometry. A total of 26 large scale two-dimensional gels of hepatic ER were used to identify 34 differentially expressed hepatic ER protein spots observed to be at least 2-fold differentially expressed with fructose feeding and the onset of insulin resistance. Differentially expressed proteins were identified by matrix-assisted laser desorption ionization-quadrupole time of flight (MALDI-Q-TOF), MALDI-TOF-postsource decay, and database mining using ProteinProspector MS-fit and MS-tag or the PROWL ProFound search engine using a focused rodent or mammalian search. Hepatic ER proteins ER60, ERp46, ERp29, glutamate dehydrogenase, and TAP1 were shown to be more than 2-fold down-regulated, whereas -glucosidase, P-glycoprotein, fibrinogen, protein disulfide isomerase, GRP94, and apolipoprotein E were all found to be up-regulated in the hepatic ER of the fructose-fed hamster. Seven isoforms of ER60 in the hepatic ER were all shown to be down-regulated at least 2-fold in hepatocytes from fructosefed/insulin-resistant hamsters. Implications of the differential expression of positively identified protein factors in the development of hepatic insulin resistance and lipoprotein abnormalities are discussed.

Received for publication, November 27, 2004 , and in revised form, March 1, 2005.

^* This work was supported in part by Operating Grant T-5323 from the Heart and Stroke Foundation of Ontario (to K. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of the Banting and Best Diabetes Center Yow Kam-Yuen graduate scholarship in diabetes research.

^|| To whom correspondence should be addressed: Division of Clinical Biochemistry, DPLM, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1X8, Canada. Tel.: 416-813-8682; Fax: 416-813-6257; E-mail: k.adeli{at}utoronto.ca.

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