We are interested in studying the dynamic remodeling of the liver cell plasma membrane through regulated exo- and endocytosis, which is thought to play a key role in shaping hepatic transport of metabolites to meet rapidly changing physiologic demands. Normal liver function depends upon rapid and precise transport of ions and other solutes across the plasma membrane of each cell at rates >1010 ions/sec. Moreover, both the number and types of ions are modulated on a minute-to-minute basis in response to circulating hormones, substrate availability, and metabolic stimuli. Since these changes in transport directly influence transmembrane water movements, associated effects on cell volume have emerged as a critical determinant of liver cell and organ functions. Cellular models of fatty liver disease are associated with defective regulation of exocytosis and cell volume. Based on previous observations that insulin stimulates robust exocytosis and preliminary observations that intracellular fatty acids impair this response, we utilize amidorone exposure as a model to increase intracellular fatty acids in culture cells. Overnight treatment of HTC cells with amidorone increased intracellular fat content ~2 fold. Glucose production in these cells was 5-fold higher and the ability of exocytosis and Cl- insulin to suppress gluconeogenesis was markedly reduced. Notably, insulin failed to activate channel opening through a mechanism that appears to involve activation of protein kinase C (PKC). Utilizing techniques such as patch clamp, imaging and biochemical our lab interest is: 1) to assess the effects on liver cells of other models of fatty liver with emphasis on impaired insulin signaling; 2) to evaluate if agents known to improve hepatic clearance of fatty acids through effects on mitochondrial b-oxidation (metoformin, tioglitazones, over-expression of carnitine palmitoyltransferase 1 (CPT1)) reverse the insulin?resistant phenotype; and 3) to asses the effects of fatty acids on the cellular content and localization of PKC isoforms.
RESEARCH INTERESTS
Metabolism
Fatty liver
RECENT PUBLICATIONS
Brown N, Mullur RS, Subramanian I, Esser V, Bennet MJ, Saudubray J-M, Feigenbaum AS, Kobari JA, Macleod PM, McGarry JD and Cohen JC., "Molecular characterization of liver-type carnitine palmitoyltransferase (L-CPT I) deficiency in six patients." J Lipid Res, 42:1134-1142, 2001
Puljak L, Pagliassotti MJ, Wei Y, Qadri I, Parameswara V, Esser V, Fitz JG and Kilic G, "Inhibition of cellular responses to insulin in a rat liver cell line. A role for PKC in insulin resistance" J Physiol., 563:471-82, 2005
Hsiao YS, Jogl G, Esser V, Tong L, "Crystal structure of rat carnitine palmitoyltransferase II (CPT-II)" Biochem Biophys Res Commun., 346:974-980, Winter 2006
Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE, Mangelsdorf DJ, Kliewer SA., "Endocrine Regulation of the Fasting Response by PPARalpha-Mediated Induction of Fibroblast Growth Factor 21." Cell Metab., 5:415-425., June 2007
SIGNIFICANT PUBLICATIONS
Esser V, Kuwajima M, Britton CH, Krishnan K, Foster DW and McGarry JD, "Inhibitors of Mitochondrial Carnitine Palmitoyltransferase I Limit the Action of Proteases of the Enzyme." J. Biol. Chem., 268:5810-5816, March 1993
Esser V, Britton CH, Weis BC, Foster DW and McGarry JD, "Cloning Sequencing and Expression of a cDNA Encoding Rat Liver Carnitine Palmitoyltransferase I. Direct Evidence that a Single Polypeptide is Involved in Inhibitor Interaction and Catalytic Function." J. Biol. Chem., 268:5817-5822, March 1993
Adams SH, Esser V, Brown NF, Ing NH, Johnson L, Foster DW, and McGarry JD, "Expression and Possible Role of Muscle-Type Carnitine Palmitoyltransferase I During Sperm Development in the Rat." Biol. Reprod., 59:1399-1405, July 1998
Britton CH, Schultz RA, Zhang B, Esser V, Foster DW and McGarry JD, "Human Liver Mitochondrial Carnitine Palmitoyltransferase I: Characterization of its cDNA and Chromosomal Localization and Partial Analysis of the Gene." Natl. Acad. Sci. U.S.A., 92:1984-1988, March 1995
Esser V, Brown NF, Cowan AT, Foster DW and McGarry JD, "Expression of a cDNA Isolated from Rat Brown Adipose Tissue and Heart Identifies the Product as the Muscle Isoform of Carnitine Palmitoyltransferase I (M-CPT I)." J. Biol. Chem., 271:6972-6977, March 1996
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