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Sparks Lab

Janet L. Dehoff-Sparks, Ph.D.

Ph.D. 1980
University of Pennsylvania

Professor,
Department of Pathology and Laboratory Medicine

 

Research Overview

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) [5]. 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 [8] through a process that is independent of changes in microsomal triglyceride transfer protein activity [9]. 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 [10].

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 [11], 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 [12]. This suggests that increased hepatic secretion of lipoproteins may be a component of the acute phase response.

Recent Publications

1/8/2016
Sparks JD, Magra AL, Chamberlain JM, O'Dell C, Sparks CE. "Insulin dependent apolipoprotein B degradation and phosphatidylinositide 3-kinase activation with microsomal translocation are restored in McArdle RH7777 cells following serum deprivation." Biochemical and biophysical research communications.. 2016 Jan 8; 469(2):326-31. Epub 2015 Nov 23.

10/2014
Yu IC, Lin HY, Sparks JD, Yeh S, Chang C. "Androgen receptor roles in insulin resistance and obesity in males: the linkage of androgen-deprivation therapy to metabolic syndrome." Diabetes.. 2014 Oct 0; 63(10):3180-8.

6/2014
Huang CK, Pang H, Wang L, Niu Y, Luo J, Chang E, Sparks JD, Lee SO, Chang C. "New therapy via targeting androgen receptor in monocytes/macrophages to battle atherosclerosis." Hypertension.. 2014 Jun 0; 63(6):1345-53. Epub 2014 Mar 31.

6/2014
Sparks CE, Corsetti JP, Sparks JD. "High-density lipoproteins: taking the good with the bad." Current opinion in lipidology.. 2014 Jun 0; 25(3):230-2.

2014
Greene MW, Burrington CM, Lynch DT, Davenport SK, Johnson AK, Horsman MJ, Chowdhry S, Zhang J, Sparks JD, Tirrell PC. "Lipid metabolism, oxidative stress and cell death are regulated by PKC delta in a dietary model of nonalcoholic steatohepatitis." PloS one. 2014 9(1):e85848. Epub 2014 Jan 15.

10/2013
Sparks CE, Sparks JD. "Hepatic postprandial transition and very low-density lipoprotein biogenesis." Current opinion in lipidology.. 2013 Oct 0; 24(5):450-2.

6/14/2013
Sparks JD, O'Dell C, Chamberlain JM, Sparks CE. "Insulin-dependent apolipoprotein B degradation is mediated by autophagy and involves class I and class III phosphatidylinositide 3-kinases." Biochemical and biophysical research communications.. 2013 Jun 14; 435(4):616-20. Epub 2013 May 15.

2/2013
Yu IC, Lin HY, Liu NC, Sparks JD, Yeh S, Fang LY, Chen L, Chang C. "Neuronal androgen receptor regulates insulin sensitivity via suppression of hypothalamic NF-?B-mediated PTP1B expression." Diabetes.. 2013 Feb 0; 62(2):411-23. Epub 2012 Nov 08.