Janet L. Dehoff-Sparks, Ph.D.
University of Pennsylvania
Department of Pathology and Laboratory Medicine
The Sparks ’ Research Laboratory, which includes Charles E. Sparks, M.D. as principle collaborator, explores the role of the liver in assembly and secretion of lipoproteins including apo B-containing lipoproteins (VLDL) and apo A-I containing lipoproteins (HDL). Our focus is on lipid metabolism and on understanding how lipoprotein secretion by the liver is regulated through transcriptional, translational and post-translational mechanisms.
Our primary research area is to completely understand the role of insulin signaling through activation of phosphatidyl inositide 3-kinases in modulating the secretion of apo B containing lipoproteins. We have found that insulin suppresses the secretion of VLDL by the liver by targeting apo B for degradation [1, 2] potentially through a quality control autophagic mechanism [3, 4].
Our laboratory is also involved in a number of collaborative projects within the University of Rochester Medical Center with investigators in the Departments of Urology and Pathology as well as the Cardiovascular Research Institute (CVRI). The Sparks Lab’s role in these collaborations is mainly on the lipoprotein metabolic aspects which in a variety of circumstances result in pathology.
One project seeks to understand the role of deficiencies of androgen receptor signaling in liver that leads to more rapid development of metabolic syndrome following androgen deprivation therapy to treat prostate cancer. This collaboration is with Dr. ShuYuan Yeh and Chawnshang Chang (Whipple Professor of Pathology), who first cloned the androgen receptor. Another project involves the role of apolipoprotein AI and HDL and the impact of apo AI modifications on integrity of endothelial cells. These studies are being carried out in collaboration with Dr. Jun-Ichi Abe at the CVRI.
An additional collaboration involves the role of testicular receptor 4 (TR4) in hepatic insulin sensitivity and lipid metabolism with a focus on stearoyl CoA desaturase (SCD-1) . SCD1 is an enzyme important in energy homeostasis and lipoprotein assembly and secretion. These studies are being carried out with Drs. Yi Fen Lee and Chang and involve increasing our understanding of the role of TR4 in transcriptional regulation of liver SCD-1.
Our laboratory utilizes a broad spectrum of techniques in our investigations including SDS-PAGE, lipoprotein fractionation techniques by HPLC and ultracentrifugation, western immunoblotting, immunoprecipitation, in vivo lipoprotein production studies, PI 3-kinase assays, apo B radioimmunoassay, ELISAs, reporter assays, Q-RT-PCR, northern blotting methods, nuclear run-on assays, tissue culture, primary hepatocyte culture systems, subcellular fractionations, polysome preparations and double labeling techniques.
We first described the mechanism responsible for insulin-mediated suppression of hepatic VLDL production which occurs through degradation of its integral protein, apo B [1, 6, 7]. We recently showed that this process was dependent upon activation and translocation of PI 3-kinase  through a process that is independent of changes in microsomal triglyceride transfer protein activity . These findings build on earlier discoveries made by Dr. Charles Sparks on the two forms of apo B (B48 and B100) and their metabolic heterogeneity .
Our laboratory also was first to document that fatty acids, which are known to stimulate VLDL secretion, under certain circumstances can inhibit the secretion of VLDL , and contribute to the development of lipid accumulation in liver which can ultimately lead to ER stress. We recently demonstrated that interleukin-6, a gp130 cytokine, is capable of stimulating apob gene transcription which increases secretion of apo B-containing lipoproteins . This suggests that increased hepatic secretion of lipoproteins may be a component of the acute phase response.
Sparks JD, Sparks CE. Insulin modulation of hepatic synthesis and secretion of apolipoprotein B by rat hepatocytes. J Biol Chem 1990; 265:8854-8862.
Sparks JD, Sparks CE, Miller LL. Insulin effects on apolipoprotein B production by normal, diabetic and treated-diabetic rat liver and cultured rat hepatocytes. Biochem J 1989; 261:83-88.
Sparks JD, Sparks CE. Overindulgence and metabolic syndrome: is FoxO1 a missing link? J Clin Invest 2008; 118:2012-2015.
Sparks JD, Dong HH. FoxO1 and hepatic lipid metabolism. Curr Opin Lipidol 2009; 20:217-226.
Kim E, Liu NC, Yu IC et al. Metformin Inhibits Nuclear Receptor TR4-Mediated Hepatic Stearoyl-CoA Desaturase 1 Gene Expression With Altered Insulin Sensitivity. Diabetes 2011; 60:1493-1503.
Bjornsson OG, Duerden JM, Bartlett SM et al. The role of pancreatic hormones in the regulation of lipid storage, oxidation and secretion in primary cultures of rat hepatocytes. Short- and long-term effects. Biochem J 1992; 281 ( Pt 2):381-386.
Sparks JD, Phung TL, Bolognino M, Sparks CE. Insulin-mediated inhibition of apolipoprotein B secretion requires an intracellular trafficking event and phosphatidylinositol 3-kinase activation: studies with brefeldin A and wortmannin in primary cultures of rat hepatocytes. Biochem J 1996; 313 ( Pt 2):567-574.
Phung TL, Roncone A, Jensen KL et al. 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 1997; 272:30693-30702.
Sparks JD, Chamberlain JM, O'Dell C et al. Acute suppression of apo B secretion by insulin occurs independently of MTP. Biochem Biophys Res Commun 2011; 406:252-256.
Sparks CE, Marsh JB. Metabolic heterogeneity of apolipoprotein B in the rat. J Lipid Res 1981; 22:519-527.
Sparks JD, Collins HL, Sabio I et al. Effects of fatty acids on apolipoprotein B secretion by McArdle RH-7777 rat hepatoma cells. Biochim Biophys Acta 1997; 1347:51-61.
Sparks JD, Cianci J, Jokinen J et al. Interleukin-6 mediates hepatic hypersecretion of apolipoprotein B. Am J Physiol Gastrointest Liver Physiol 2010; 299:G980-989.