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Janet D. Sparks, Ph.D.

Associate Professor of Pathology and Laboratory Medicine

Insulin Regulation of Hepatic Lipoprotein Production
Through Phosphatidylinositide-3-Kinase Activation
Via Insulin Receptor Signaling Pathways

URMC Labs
601 Elmwood Ave., Rm B7653
Rochester, NY 14642-8626
Tel: (585) 275-7755
Fax: (585) 756-5337

Janet_Sparks@urmc.rochester.edu

Qualifications

Ph.D., Pathology, University of Pennsylvania 1980
Predoctoral Fellow, Wistar Institute of Anatomy and Biology, Philadelphia 1975-80
Postdoctoral Fellow, Wistar Institute of Anatomy and Biology, Philadelphia 1981-82
Postdoctoral Fellow, Pathology, University of Rochester 1983-85

Research Overview

Plasma lipoproteins are the major vehicles for non-aqueous transport of lipids, including cholesterol and triglyceride, and lipid-soluble vitamins such as vitamin A and E, from the liver and intestine to tissues. Derangements in lipoprotein metabolism are involved in progression of atherosclerosis, an underlying cause of heart disease and strokes which remain the major cause of death in the United States. Insulin, known as a key regulator in carbohydrate metabolism, plays a major regulatory role in hepatic lipoprotein metabolism. Insulin acts by inhibition of secretion of triglyceride-rich lipoproteins through a mechanism involving the stimulation of the intracellular degradation of apolipoprotein B, an essential structural apolipoprotein. Research in my laboratory links specific events involved in insulin receptor (IR) signal transduction with microsomal events that lead to degradation of apo B. The focus is on insulin-activated phosphatidylinositide 3-kinase (PI-3-kinase) in the translocation of apo B and its intracellular transport within the secretory pathway. Investigations employ primary rat hepatocytes, McArdle RH-7777 rat hepatoma cells and HepG2 cells and assay of IR signaling, Beta-subunit phosphorylation, IRS phosphorylation, PI 3-K activation and of PI 3-K mass in subcellular fractions. Progress will allow better understanding of insulin regulation of triglyceride-rich lipoprotein secretion by liver and will provide insights into the mechanisms involved in the development of hypertriglyceridemia in human obesity and insulin resistance syndromes such as metabolic Syndrome X which increase the risk of atherosclerosis complications up to ten times.

Publications

CHIRIEAC DV, COLLINS HL, CIANCI J, SPARKS JD, and SPARKS CE. Altered triglyceride-rich lipoprotein production in Zucker diabetic fatty rats. Am J Physiol Endocrinol Metab. 287(1):E42-9 (2004). (PubMed)

AU CS, WAGNER A, CHONG T, QIU W, SPARKS JD, ADELI K. Insulin regulates hepatic apolipoprotein B production independent of the mass or activity of Akt1/PKBalpha. Metabolism. 53(2):228-35 (2004). (PubMed)

CHIRIEAC DV, CIANCI J, COLLINS HL, SPARKS JD, SPARKS CE: Insulin suppression of VLDL apo B secretion is not mediated by the LDL receptor. Biochem. Biopys. Res. Commun. 297: 134-137 (2002).

FISHER EA, CHEN X, PAN M, WU X, WANG H, JAMIL H, SPARKS JD, WILLIAMS KJ: The triple threat to nascent apolipoprotein B: Evidence for multiple, distinct degradative pathways. J. Biol. Chem. 276:27855-27863 (2001).

CHIRIEAC DV (post-doctoral fellow) CHIRIEAC LR, CORSETTI JP, CIANCI J, SPARKS CE and SPARKS JD: Glucose-stimulated insulin secretion suppresses hepatic triglyceride-rich lipoprotein and apo B production in vivo. Amer. J. Physiol. 279: E1001-E1011 (2000).

COLLINS HL (pre-doctoral fellow), SPARKS CE and SPARKS JD: B48 is preferentially translated over B100 in McArdle RH-7777 cells expressing increased endogenous apo B mRNA. Biochem. Biphys. Res. Commun. 273: 1156-1160 (2000).

SPARKS JD, SHAW WN, BOLOGNINO M, CORSETTI JP, PESEK JF and SPARKS CE: Insulin-treated Zucker diabetic fatty rats retain the hypertriglyceridemia associated with obesity. Metabolism (2000).

Sparks JD, Bolognino M, Khurana R, Peterson RG, Corsetti JC and Sparks CE: Lipoprotein alterations in 10 and 20 week Zucker diabetic fatty rats: hyperinsulinemic versus insulinopenic hyperglycemia. Metabolism 47: 1315-1324 (1998).

PHUNG TL (pre-doctoral fellow), RONCONE A, DE MESY JENSEN KL, SPARKS CE and SPARKS JD: Phosphoinositide 3-kinase activity is necessary for insulin-dependent inhibition of apolipoprotein B secretion by rat hepatocytes and localizes to the endoplasmic reticulum. J. Biol. Chem. 272: 30693-30702 (1997).

SPARKS JD, PHUNG TL (pre-doctoral fellow), BOLOGNINO M and SPARKS CE: Insulin-mediated inhibition of apo-lipoprotein B secretion requires an intracellular trafficking event and phosphatidylinositol 3-kinase activation. Studies using brefeldin A and wortmannin in primary cultures of rat hepatocytes. Biochem. J. 313: 567-574 (1996).

SPARKS JD and SPARKS CE: Insulin regulation of triacylglycerol-rich lipoprotein synthesis and secretion. Biochem. Biophys. Acta 1215: 9-32 (1994). Review article.