Insulin resistance, hepatic inflammation, and NAFLD are interlocking pathophysiologic events, but the mechanisms of these abnormalities, and the ways in which these different processes interact, are poorly understood. This is a broad, collaborative application in which the four participating PI's and laboratories will concentrate their focus on the etiology and pathophysiology of hepatic inflammation, steatosis, and insulin resistance. The scale of this application is substantial and will focus on four overall specific aims. In the first aim, an ambitious, large scale time course will be undertaken in high fat diet (HFD)/obese mice, coupled with systematic in vitro and in vivo measurements to uncover the dynamic temporal time course and key transition points enabling the development of hepatic insulin resistance/inflammation/steatosis.
The second aim explores a novel hypotheses which proposes that changes in intestinal microflora and gut permeability to bacterial products triggers inflammatory signals directed to the liver. These inflammatory stimuli then interact with immune cells in the liver, generating the chronic hepatic inflammatory state.
The third aim encompasses several new ideas and hypotheses aimed at delineating the molecular mechanisms underlying the metabolic disturbances in the liver. These studies will involve tracking the itinerary of immune cells to the liver, identifying the phenotypic function of the different liver cell types, studies of biochemical pathways involved in insulin signaling, lipogenesis/fat oxidation, inflammation, and the identification of transcription factor cistromes and epigenetic changes in genomic loci induced by obesity. In vivo and in vitro studies in a number of knockout mice will be heavily used in the pursuit of these studies.
The final aim proposes translational studies in which liver biopsies will be obtained from obese NAFLD subjects before and after weight loss. Cellular, biochemical, and genomic studies will be performed in these biopsies and correlated with the in vivo clinical data on these patients. In this way, we will be able to test the ideas and concepts learned from the basic studies in the first three aims for relevance to human pathophysiology.

Public Health Relevance

NAFLD is closely associated with hepatic insulin resistance and inflammation and is the most common liver disease in the US. The pathophysiologic mechanisms underlying the interactions between hepatic insulin resistance, inflammation, and steatosis are poorly understood, and this project should lead to a greatly improved basic understanding of this disorder with the potential to lead to new therapeutic opportunities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Resource-Related Research Projects (R24)
Project #
5R24DK090962-02
Application #
8152191
Study Section
Special Emphasis Panel (ZDK1-GRB-2 (O3))
Program Officer
Abraham, Kristin M
Project Start
2010-09-30
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$745,195
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Saison-Ridinger, Maya; DelGiorno, Kathleen E; Zhang, Tejia et al. (2017) Reprogramming pancreatic stellate cells via p53 activation: A putative target for pancreatic cancer therapy. PLoS One 12:e0189051
Fan, Weiwei; Waizenegger, Wanda; Lin, Chun Shi et al. (2017) PPAR? Promotes Running Endurance by Preserving Glucose. Cell Metab 25:1186-1193.e4
Doktorova, Marcela; Zwarts, Irene; Zutphen, Tim van et al. (2017) Intestinal PPAR? protects against diet-induced obesity, insulin resistance and dyslipidemia. Sci Rep 7:846
Wang, Jianrong; He, Nanhai; Zhang, Na et al. (2017) NCoR1 restrains thymic negative selection by repressing Bim expression to spare thymocytes undergoing positive selection. Nat Commun 8:959
Dickey, Audrey S; Sanchez, Dafne N; Arreola, Martin et al. (2017) PPAR? activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis. Sci Transl Med 9:
De Magalhaes Filho, C Daniel; Downes, Michael; Evans, Ronald M (2017) Farnesoid X Receptor an Emerging Target to Combat Obesity. Dig Dis 35:185-190
Chung, Hyo Kyun; Ryu, Dongryeol; Kim, Koon Soon et al. (2017) Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis. J Cell Biol 216:149-165
Oral, Elif A; Reilly, Shannon M; Gomez, Andrew V et al. (2017) Inhibition of IKK? and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes. Cell Metab 26:157-170.e7
Wu, Chyuan-Chuan; Baiga, Thomas J; Downes, Michael et al. (2017) Structural basis for specific ligation of the peroxisome proliferator-activated receptor ?. Proc Natl Acad Sci U S A 114:E2563-E2570
Sherman, Mara H; Yu, Ruth T; Tseng, Tiffany W et al. (2017) Stromal cues regulate the pancreatic cancer epigenome and metabolome. Proc Natl Acad Sci U S A 114:1129-1134

Showing the most recent 10 out of 72 publications