Paul F. Pilch
Boston University School of Medicine
Silvio Conte Building, K603
72 E. Concord Street
Boston, MA 02118
Lab Phone: 617-638-4045
Joint Appointment: Department of Medicine
BA, Temple University, Philadelphia, PA
PhD, Purdue University, W. Lafayette, IN
Cell biology of fuel utilization in adipocytes and skeletal muscle.
The modern Western diet coupled with a sedentary lifestyle has led to an epidemic of obesity, a consequence of which is a dramatic rise in the incidence of type II diabetes mellitus, a malfunction in insulin-regulated metabolism. At the cellular level, type II diabetes is characterized by failure of insulin to act in liver, muscle and fat. We study aspects of insulin signaling and action in the latter two tissues. Insulin resistance in muscle (and fat) derives from the failure of insulin to activate the tissue-specific glucose transporter GLUT4. The activation mechanism for this process involves vesicle trafficking and protein targeting with regard to GLUT4 and the insulin receptor. We are characterizing the formation and protein content of GLUT4-containing vesicles; we are trying to identify the organelles through which they pass on their way to and from the cell surface and we are determining the communication mechanism(s) (signaling) from the insulin receptor to the GLUT4-containing vesicles. These studies involve both fat and muscle cells, and we are also studying the physiological role of cell surface (plasma membrane) micro-domains called caveolae that are particularly abundant in these tissues. We have evidence for the hypothesis that caveolae (for little caves that are small invaginations of the plasma membrane into the cytosol) are involved in lipid trafficking.
We continue to study other aspects of adipocyte and muscle cell biology to understand the interplay between glucose and fat metabolism as well as the interplay between adipocytes and muscle required for overall metabolic homeostasis. Indeed, we wish to uncover the mechanism(s) by exercise also regulates some of these same parameters independent of insulin. Understanding these pathways will help us to figure out how they are compromised in pathophysiological states such as diabetes.
- Caveolin-1 is necessary for hepatic oxidative lipid metabolism: evidence for crosstalk between caveolin-1 and bile acid signaling. Fernández-Rojo MA, Gongora M, Fitzsimmons RL, Martel N, Martin SD, Nixon SJ, Brooks AJ, Ikonomopoulou MP, Martin S, Lo HP, Myers SA, Restall C, Ferguson C, Pilch PF, McGee SL, Anderson RL, Waters MJ, Hancock JF, Grimmond SM, Muscat GE, Parton RG. Cell Rep. 2013 Jul 25;4(2):238-47. doi: 10.1016/j.celrep.2013.06.017. Epub 2013 Jul 11.
- IDOL Stimulates Clathrin-Independent Endocytosis and Multivesicular Body-Mediated Lysosomal Degradation of the Low-Density Lipoprotein Receptor. Scotti E, Calamai M, Goulbourne CN, Zhang L, Hong C, Lin RR, Choi J, Pilch PF, Fong LG, Zou P, Ting AY, Pavone FS, Young SG, Tontonoz P. Mol Cell Biol. 2013 Apr;33(8):1503-14. doi: 10.1128/MCB.01716-12. Epub 2013 Feb 4.
- Co-regulation of cell polarization and migration by caveolar proteins PTRF/Cavin-1 and caveolin-1. Hill MM, Daud NH, Aung CS, Loo D, Martin S, Murphy S, Black DM, Barry R, Simpson F, Liu L, Pilch PF, Hancock JF, Parat MO, Parton RG. PLoS One. 2012;7(8):e43041. doi: 10.1371/journal.pone.0043041.
- Cholesterol depletion in adipocytes causes caveolae collapse concomitant with proteosomal degradation of cavin-2 in a switch-like fashion. Breen MR, Camps M, Carvalho-Simoes F, Zorzano A, Pilch PF. PLoS One. 2012;7(4):e34516. Epub 2012 Apr 6.
- Caveolae, fenestrae and transendothelial channels retain PV1 on the surface of endothelial cells. Tkachenko E, Tse D, Sideleva O, Deharvengt SJ, Luciano MR, Xu Y, McGarry CL, Chidlow J, Pilch PF, Sessa WC, Toomre DK, Stan RV. PLoS One. 2012;7(3):e32655.
- Caveolins/caveolae protect adipocytes from fatty acid-mediated lipotoxicity. Meshulam T, Breen MR, Liu L, Parton RG, Pilch PF. J Lipid Res. 2011 Aug;52(8):1526-32. Epub 2011 Jun 7.
- Caveolae and lipid trafficking in adipocytes. Pilch PF, Meshulam T, Ding S, Liu L. Clin Lipidol. 2011;6(1):49-58.
- Fat caves: caveolae, lipid trafficking and lipid metabolism in adipocytes. Pilch PF, Liu L. Trends Endocrinol Metab. 2011 Aug;22(8):318-24. Epub 2011 May 17. Review.
- The sugar is sIRVed: sorting Glut4 and its fellow travelers. Kandror KV, Pilch PF. Traffic. 2011 Jun;12(6):665-71. doi: 10.1111/j.1600-0854.2011.01175.x.
- Jedrychowski MP, Gartner CA, Gygi SP, Zhou L, Herz J, Kandror KV, Pilch PF. (2010) Proteomic analysis of GLUT4 storage vesicles reveals LRP1 to be an important vesicle component and target of insulin signaling. J Biol Chem. 285:104-14.
- Simard JR, Meshulam T, Pillai BK, Kirber MT, Brunaldi K, Xu S, Pilch PF, Hamilton JA. (2010) Caveolins sequester fatty acids on the cytoplasmic leaflet of the plasma membrane, augment triglyceride formation and protect cells from lipotoxicity. J Lipid Res. 51: 914-922.
- Bastiani M, Liu L, Hill MM, Jedrychowski MP, Nixon SJ, Lo HP, Abankwa D, Luetterforst R, Fernandez-Rojo M, Breen MR, Gygi SP, Vinten J, Walser PJ, North KN, Hancock JF, Pilch PF, Parton RG. (2009) MURC/Cavin-4 and cavin family members form tissue-specific caveolar complexes. J Cell Biol. 185:1259-73
- Chao LC, Wroblewski K, Zhang Z, Pei L, Vergnes L, Ilkayeva OR, Ding S, Reue K, Watt MJ, Newgard CB, Pilch PF, Hevener AL, Tontonoz P. (2009) Insulin resistance and altered systemic glucose metabolism in mice lacking Nur77. Diabetes. 58:2788-96.
- Liu L, Brown D, McKee M, Lebrasseur NK, Yang D, Albrecht KH, Ravid K, Pilch PF. (2008). Deletion of Cavin/PTRF causes global loss of caveolae, dyslipidemia, and glucose intolerance. Cell Metab. 8:310-7
- Liu L and Pilch P.F.( 2008) A critical role of cavin (PTRF) in caveolae formation and organization. J Biol Chem. 283, 4314-4322.
- Saito, T., Jones, C.C., Huang, S., Czech, M.P. and Pilch, P.F. (2007) The interaction of AKT with APPL1 is required for insulin-stimulated Glut4 translocation. J Biol Chem. 2007 Sep 11; [Epub ahead of print].
- Chao LC, Zhang Z, Pei L, Saito T, Tontonoz P, Pilch PF. (2007) Nur77 coordinately regulates expression of genes linked to glucose metabolism in skeletal muscle. Mol Endocrinol. 21, 2152-2163.
- Pilch PF, Souto RP, Liu L, Jedrychowski MP, Berg EA, Costello CE, Gygi SP. (2007) Cellular spelunking: exploring adipocyte caveolae. J Lipid Res. 48, 2103-2111