There are three major OBJECTIVES in this application, each of which addresses pathways of hepatic lipid metabolism implicated in human disease. The first objective is to advance understanding of cell specific (hepatocyte versus stellate cell) lipid droplet composition and turnover in modulating hepatic fibrogenesis. The second objective is to understand how genetic modifiers of hepatic VLDL assembly regulate lipid droplet formation and fibrogenic signaling. The third objective is to understand how genetic modifiers of VLDL assembly and of fatty acid uptake also modify canalicular cholesterol secretion and gallstone susceptibility. The BACKGROUND to the current proposal is based on key published and preliminary findings implicating lipid droplet formation and fibrogenic signaling and also data linking pathways of VLDL assembly to gallstone susceptibility.
The AIMS of this proposal will test the following HYPOTHESES. Based on observations that germline L-Fabp deletion attenuates lipid droplet formation in both hepatocytes and stellate cells, AIM (1) will test the hypothesis that L-Fabp modulates lipid droplet formation and fibrogenesis associated with steatosis via cell specific pathways. Based on observations that germline L-Fabp deletion attenuates hepatic lipid droplet formation and steatosis in the setting of liver-specific Mttp deletion and also attenuates hepatic fibrosis associated with high trans fat fructose feeding, AIM (2) will test the hypothesis that VLDL assembly pathways modulate lipid droplet formation, FA trafficking and fibrogenic signaling.
AIM 2 will also examine iPS derived human hepatocyte like cells. Based on observations that liver-specific Mttp deletion attenuates gallstone formation in both the wild type and L-Fabp knockout background, AIM (3) will test the hypothesis that Mttp modifies canalicular cholesterol flux in addition to VLDL secretion. Based on other observations that CD36 deletion attenuates gallstone formation in both wild type and L-Fabp knockout background, AIM (3) will also test the hypothesis that CD36 modifies canalicular cholesterol secretion. Taken together, these studies address key issues in understanding the pathways that mediate progression of benign hepatic steatosis to fibrogenic liver injury, including the lipid mediators associated with lipid droplets. These studies also address key pathways in the genetic regulation of canalicular lipid transport and cholesterol gallstone susceptibility.
Innovation and health relevance of this proposal This renewal application will examine critical pathways and genes that regulate fat metabolism in the liver and which can lead to liver fibrosis and/or cholesterol gallstones, both prevalent diseases associated with obesity and diabetes. We will use novel mouse strains and human liver-like cells to understand how specific genes that regulate the formation of fat droplets in liver cells work to decrease liver injury. Our studies wil also use novel mouse strains to understand the pathways leading to cholesterol gallstone disease.
|Xie, Yan; Cifarelli, Vincenza; Pietka, Terri et al. (2017) Cd36 knockout mice are protected against lithogenic diet-induced gallstones. J Lipid Res 58:1692-1701|
|Wen, Yahong; Liao, Grace; Pritchard, Thomas et al. (2017) A stable but reversible integrated surrogate reporter for assaying CRISPR/Cas9-stimulated homology-directed repair. J Biol Chem 292:6148-6162|
|Ratnapradipa, Kendra L; Lian, Min; Jeffe, Donna B et al. (2017) Patient, Hospital, and Geographic Disparities in Laparoscopic Surgery Use Among Surveillance, Epidemiology, and End Results-Medicare Patients With Colon Cancer. Dis Colon Rectum 60:905-913|
|Cifarelli, Vincenza; Ivanov, Stoyan; Xie, Yan et al. (2017) CD36 deficiency impairs the small intestinal barrier and induces subclinical inflammation in mice. Cell Mol Gastroenterol Hepatol 3:82-98|
|Newberry, Elizabeth P; Xie, Yan; Kennedy, Susan M et al. (2017) Prevention of hepatic fibrosis with liver microsomal triglyceride transfer protein deletion in liver fatty acid binding protein null mice. Hepatology 65:836-852|
|Lo, Hei-Yong G; Jin, Ramon U; Sibbel, Greg et al. (2017) A single transcription factor is sufficient to induce and maintain secretory cell architecture. Genes Dev 31:154-171|
|Davidson, Nicholas O; El-Serag, Hashem B (2017) How to Prepare for and Write a Grant: Personal Perspectives. Gastroenterology 152:7-11|
|Nalbantoglu, ILKe; Blanc, Valerie; Davidson, Nicholas O (2016) Characterization of Colorectal Cancer Development in Apc (min/+) Mice. Methods Mol Biol 1422:309-27|
|DeBosch, Brian J; Heitmeier, Monique R; Mayer, Allyson L et al. (2016) Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis. Sci Signal 9:ra21|
|Carouge, Delphine; Blanc, Valerie; Knoblaugh, Sue E et al. (2016) Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias. Proc Natl Acad Sci U S A 113:E5425-33|
Showing the most recent 10 out of 117 publications