There is a fundamental gap in our understanding of how diet and nutrients induce variation in signaling pathways and mechanisms to initiate alterations in translational control of hepatic gene expression that contribute to the pathogenesis of fatty liver disease. Continued existence of this gap represents an important problem because, until it is filled, understanding the etiology of fatty liver disease and developing interventions o prevent or reverse it will remain largely unfulfilled. Our long-term goal is to better understand te translational control of gene expression in the liver. The objective of the project proposed in thi application is to characterize translational control mechanisms and protein expression patterns that undergo acute variation in response to initiating consumption of a diet high in sugar and saturated fat (i.e. a Western diet). Our central hypothesis is that acute variation in protein expression in response to the diet is mediated through mechanisms involving the function of eIF4F and the 43S preinitiation complex. The rationale for the proposed research is that understanding diet-induced acute variation in these mechanisms has the potential to translate into better under-standing the pathogenesis of non-alcoholic fatty liver disease, a condition that affects about one-third of the US population. Guided by strong and in some cases novel preliminary findings, the hypothesis will be tested in the liver of mice following initiation of consumption of a Western diet by pursuing the following three specific aims: 1) Define variation in mTORC1 signaling and protein expression patterns; 2) Characterize expression and covalent modification (i.e. phosphorylation and O-GlcNAcylation) of initiation factors involved in assembly and function of eIF4F; and 3) Assess phosphorylation of the a-subunit of eIF2 as well as phosphorylation and GEF activity of eIF2B. Under the first aim, a novel mechanism suggested by our preliminary data for the Rheb- and Rag-mediated inputs to mTORC1 will be explored to develop an understanding of how the Western diet affects this hormone and nutrient sensing pathway. In addition, a recently developed technology that is now established in our laboratory will be used to identify variation in protein expression patterns. Under the second aim, we will extend our recent discovery of hyperglycemia-mediated O-GlcNAcylation of 4E-BP1 and eIF4G to studies on its role in regulating assembly and function of the eIF4F complex. Under the third aim, we will rely on our extensive experience in studies on assembly of the 43S preinitiation complex to gain an understanding of the relative roles of PERK and/or PKR-dependent phosphorylation of eIF2a and a corresponding reduction in eIF2B activity in protein expression from mRNAs with upstream open reading frames. The proposed research is significant because it is expected to advance and expand our understanding of how diet and nutrients can mediate variation in the patterns of gene expression in the liver leading to maladapted metabolism. Ultimately, such knowledge has the potential to inform development of both dietary counseling and pharmacologic intervention to prevent or reverse fatty liver disease.

Public Health Relevance

The proposed research is relevant to public health because discovery of mechanisms that initiate changes in translational control of hepatic gene expression in response to consumption of excess nutrients, particularly diets high in sugar and saturated fats, is expected to increase understanding of the pathogenesis of non- alcoholic fatty liver disease, a chronic condition that affects approximately one-third of the US population. Thus, the proposed research is relevant to the part of the NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of the current epidemic of obesity and type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK013499-48
Application #
9304191
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Silva, Corinne M
Project Start
1996-09-01
Project End
2019-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
48
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Physiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Dai, Weiwei; Miller, William P; Toro, Allyson L et al. (2018) Deletion of the stress-response protein REDD1 promotes ceramide-induced retinal cell death and JNK activation. FASEB J :fj201800413RR
Guan, Bo-Jhih; van Hoef, Vincent; Jobava, Raul et al. (2017) A Unique ISR Program Determines Cellular Responses to Chronic Stress. Mol Cell 68:885-900.e6
Pettit, Ashley P; Jonsson, William O; Bargoud, Albert R et al. (2017) Dietary Methionine Restriction Regulates Liver Protein Synthesis and Gene Expression Independently of Eukaryotic Initiation Factor 2 Phosphorylation in Mice. J Nutr 147:1031-1040
Miller, William P; Ravi, Suhana; Martin, Tony D et al. (2017) Activation of the Stress Response Kinase JNK (c-Jun N-terminal Kinase) Attenuates Insulin Action in Retina through a p70S6K1-dependent Mechanism. J Biol Chem 292:1591-1602
Kimball, Scot R (2017) Leucine-Induced Upregulation of Terminal Oligopyrimidine mRNA Translation in Skeletal Muscle: Just the Tip of the Iceberg? J Nutr 147:1603-1604
Black, Adam J; Gordon, Bradley S; Dennis, Michael D et al. (2016) Regulation of protein and mRNA expression of the mTORC1 repressor REDD1 in response to leucine and serum. Biochem Biophys Rep 8:296-301
Gordon, Bradley S; Steiner, Jennifer L; Williamson, David L et al. (2016) Emerging role for regulated in development and DNA damage 1 (REDD1) in the regulation of skeletal muscle metabolism. Am J Physiol Endocrinol Metab 311:E157-74
Kimball, Scot R; Gordon, Bradley S; Moyer, Jenna E et al. (2016) Leucine induced dephosphorylation of Sestrin2 promotes mTORC1 activation. Cell Signal 28:896-906
Miller, William P; Mihailescu, Maria L; Yang, Chen et al. (2016) The Translational Repressor 4E-BP1 Contributes to Diabetes-Induced Visual Dysfunction. Invest Ophthalmol Vis Sci 57:1327-37
Dennis, Michael D; Kimball, Scot R; Fort, Patrice E et al. (2015) Regulated in development and DNA damage 1 is necessary for hyperglycemia-induced vascular endothelial growth factor expression in the retina of diabetic rodents. J Biol Chem 290:3865-74

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