Nonalcoholic fatty liver disease (NAFLD) is a significant risk factor for the development of hepatic insulin resistance and type 2 diabetes and is also linked to the development of other serious liver disease states including steatohepatitis, cirrhosis, and hepatic carcinoma. NAFLD is recognized as a significant health problem in the VA population. Our previous results show that mitochondrial function is linked to the development of NAFLD. Unfortunately, the mechanism(s) that govern hepatic mitochondrial function and thus alter susceptibility for hepatic steatosis remain largely unknown. Peroxisome proliferator-activated gamma co-activator alpha (PGC-1?) co-activates nuclear transcriptional factors resulting in increased mitochondrial biogenesis. Both PGC-1? and mitochondrial function are suppressed in obesity. In contrast, we have shown that in vivo liver-specific PGC-1? overexpression (o/e) increases mitochondrial function and reduces hepatic lipid accumulation. But these results may not be solely attributable to increased mitochondrial biogenesis. Recent data shows that maintenance of high quality mitochondria is also dependent on the turnover and degradation of low functioning or damaged mitochondria in the lysosome by a process termed mitophagy (i.e. autophagy of mitochondria). To that end we found that PGC-1? overexpression also increased markers of autophagy, a link that has never before been examined. This proposal will test the primary hypothesis that PGC- 1? plays a primary role in mediating a coordinated co-activation of mitochondrial biogenesis and mitophagy that is necessary for maintaining mitochondrial function and preventing and treating NAFLD. Rodent models that possess defects in mitochondrial biogenesis or mitophagy due to specific genetic alterations will be used to test the importance of the respective pathways. We will also use molecular gain of function therapy (overexpression of PGC-1?) and exercise training to modulate pathways, in addition to performing in-vitro primary hepatocyte studies to isolate hepatic specific mechanism(s) and examine acute molecular changes that underlie whole body results.
The specific aims will: 1) Determine if impaired capacity for mitochondrial biogenesis and mitophagy increases susceptibility for hepatic steatosis and insulin resistance due to reduced mitochondrial function, and 2). Test if increased mitophagy and mitochondrial function are necessary for treatment of hepatic steatosis and insulin resistance.

Public Health Relevance

Currently, 34% of the general population and 75-100% of obese and extremely obese individuals are estimated to have non-alcoholic fatty liver disease (NAFLD). NAFLD increases risk for liver complications including steatohepatitis, cirrhosis, and hepatic carcinoma. NAFLD also conveys significant metabolic risk as it plays a primary role in the development of type 2 diabetes. Current estimates suggest that incidence of fatty liver and type 2 diabetes are higher in the VA population than the general population, therefore, both disease states place significant financial strain on the VA health system, and dramatically reduce the quality of life for our US Veterans. The outcomes of this study will improve our knowledge about the mechanisms of NAFLD development and highlight potential therapeutic targets for the treatment of NAFLD.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX002567-01A1
Application #
8819894
Study Section
Endocriniology A (ENDA)
Project Start
2014-10-01
Project End
2018-09-30
Budget Start
2014-10-01
Budget End
2015-09-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Harry S. Truman Memorial VA Hospital
Department
Type
DUNS #
082263013
City
Columbia
State
MO
Country
United States
Zip Code
65201
Fletcher, Justin A; Linden, Melissa A; Sheldon, Ryan D et al. (2018) Fibroblast growth factor 21 increases hepatic oxidative capacity but not physical activity or energy expenditure in hepatic peroxisome proliferator-activated receptor ? coactivator-1?-deficient mice. Exp Physiol 103:408-418
Panasevich, Matthew R; Schuster, Colin M; Phillips, Kathryn E et al. (2017) Soy compared with milk protein in a Western diet changes fecal microbiota and decreases hepatic steatosis in obese OLETF rats. J Nutr Biochem 46:125-136
Morris, Jill K; Uy, Roxanne Adeline Z; Vidoni, Eric D et al. (2017) Effect of APOE ?4 Genotype on Metabolic Biomarkers in Aging and Alzheimer's Disease. J Alzheimers Dis 58:1129-1135
Thyfault, John P; Morris, E Matthew (2017) Intrinsic (Genetic) Aerobic Fitness Impacts Susceptibility for Metabolic Disease. Exerc Sport Sci Rev 45:7-15
Porter, Jay W; Rowles 3rd, Joe L; Fletcher, Justin A et al. (2017) Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21. J Endocrinol 235:97-109
Tan, Ee Phie; McGreal, Steven R; Graw, Stefan et al. (2017) Sustained O-GlcNAcylation reprograms mitochondrial function to regulate energy metabolism. J Biol Chem 292:14940-14962
Park, Young-Min; Rector, R Scott; Thyfault, John P et al. (2016) Effects of ovariectomy and intrinsic aerobic capacity on tissue-specific insulin sensitivity. Am J Physiol Endocrinol Metab 310:E190-9
Park, Young-Min; Kanaley, Jill A; Padilla, Jaume et al. (2016) Effects of intrinsic aerobic capacity and ovariectomy on voluntary wheel running and nucleus accumbens dopamine receptor gene expression. Physiol Behav 164:383-9
Fletcher, Justin A; Linden, Melissa A; Sheldon, Ryan D et al. (2016) Fibroblast growth factor 21 and exercise-induced hepatic mitochondrial adaptations. Am J Physiol Gastrointest Liver Physiol 310:G832-43
Park, Young-Min; Kanaley, Jill A; Zidon, Terese M et al. (2016) Ovariectomized Highly Fit Rats Are Protected against Diet-Induced Insulin Resistance. Med Sci Sports Exerc 48:1259-69

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