The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH) and cirrhosis;and multiple metabolic impairments including disruption of endoplasmic reticulum (ER) homeostasis. Disruption of ER homeostasis or ER stress activates the unfolded protein response (UPR). Recent studies performed in obese, nondiabetic humans with NAFLD have observed activation of the UPR in liver and/or adipose tissue. The trigger(s) for ER stress in the liver and how ER homeostasis is linked to disease progression in NAFLD have not been determined. An additional issue in NAFLD involves identification of cellular and molecular events that change the disease from non-progressive steatosis to NASH and progressive liver disease. One cellular event that appears to be a cardinal feature of NASH is hepatocyte apoptosis. Our work over the last 4 yrs has demonstrated that delivery of long chain saturated fatty acids to liver cells or increasing the amount of saturated fatty acids within the liver provokes ER stress, apoptosis and liver injury. These studies have lead to the hypothesis that the composition of fatty acids delivered to or stored within the liver is an important determinant of ER homeostasis, hepatocyte apoptosis and disease progression in NAFLD. The focus of this application is to elucidate how saturated fatty acids disrupt ER homeostasis and to identify cellular mechanisms that link ER homeostasis to hepatocyte apoptosis and liver injury. Towards this end, the following specific aims are proposed: 1) To determine how saturated fatty acids promote ER stress, apoptosis and liver injury in vivo, 2) To determine whether saturated fatty acid-mediated ER stress, apoptosis and liver injury involves impairments in protein chaperone function, and 3) To identify cellular mechanisms linking saturated fatty acids and hepatocyte apoptosis using cell models.
Fatty liver disease is poorly understood and the factors that promote liver damage in this disease have not been identified. This application investigates the hypothesis that the amount of saturated fatty acids delivered to or stored within the liver is an important factor in disease progression.
|Pagliassotti, Michael J; Kim, Paul Y; Estrada, Andrea L et al. (2016) Endoplasmic reticulum stress in obesity and obesity-related disorders: An expanded view. Metabolism 65:1238-46|
|Wei, Yuren; Wang, Dong; Moran, Gretchen et al. (2013) Fructose-induced stress signaling in the liver involves methylglyoxal. Nutr Metab (Lond) 10:32|
|Nivala, Angela M; Reese, Lauren; Frye, Melinda et al. (2013) Fatty acid-mediated endoplasmic reticulum stress in vivo: differential response to the infusion of Soybean and Lard Oil in rats. Metabolism 62:753-60|
|Wang, Dong; Wei, Yuren; Frye, Melinda et al. (2013) Saturated Fatty Acid-induced cytotoxicity in liver cells does not involve phosphatase and tensin homologue deleted on chromosome 10. J Nutr Metab 2013:514206|
|Ellis, F; Nivala, A; Pfaffenbach, K T et al. (2012) C-reactive protein does not impair insulin suppression of glucose release in primary hepatocytes. Nutr Metab Cardiovasc Dis 22:115-9|
|Foster, Michelle T; Pagliassotti, Michael J (2012) Metabolic alterations following visceral fat removal and expansion: Beyond anatomic location. Adipocyte 1:192-199|
|Gentile, Christopher L; Nivala, Angela M; Gonzales, Jon C et al. (2011) Experimental evidence for therapeutic potential of taurine in the treatment of nonalcoholic fatty liver disease. Am J Physiol Regul Integr Comp Physiol 301:R1710-22|
|Gentile, Christopher L; Frye, Melinda A; Pagliassotti, Michael J (2011) Fatty acids and the endoplasmic reticulum in nonalcoholic fatty liver disease. Biofactors 37:8-16|
|Pfaffenbach, Kyle T; Nivala, Angela M; Reese, Lauren et al. (2010) Rapamycin inhibits postprandial-mediated X-box-binding protein-1 splicing in rat liver. J Nutr 140:879-84|
|Pfaffenbach, Kyle T; Gentile, Christopher L; Nivala, Angela M et al. (2010) Linking endoplasmic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemical chaperones in palmitate-mediated cell death. Am J Physiol Endocrinol Metab 298:E1027-35|
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