Abstract 014: Brain Endoplasmic Reticulum Stress Mediates the Development of Non-Alcoholic Fatty Liver Disease
Non-alcoholic fatty liver disease (NAFLD), characterized by an accumulation of liver lipids without excess alcohol consumption, is a major risk factor for the development of hypertension and Type-II diabetes. Liver endoplasmic reticulum (ER) stress and activation of the unfolded protein response have been implicated in the development of NAFLD. Brain ER stress has emerged as the basis of a number of chronic diseases, although the role of the central nervous system in mediating NAFLD remains unknown. We hypothesized that brain ER stress contributes to the development of NAFLD. First, male C57Bl/6 mice were instrumented with an intracerebroventricular (ICV) cannula for administration of the chemical ER stress inducer thapsigargin (TG; 1 μg/day; 3 days; n=5) or vehicle control (n=4). Daily short-term induction of ER stress in the brain with TG did not alter body weight (27±1 vs. 27±1 g; vehicle vs. TG; p>0.05), food intake or adiposity, but caused a ~40% increase in liver weight (1.04±0.03 vs. 1.39±0.10 g; vehicle vs. TG; p<0.05). ICV TG also elicited a significant increase in liver triglycerides (36±1 vs. 135±6 mmol; vehicle vs. TG; p<0.05), and real-time PCR analysis revealed upregulation of hepatic gluconeogenic and lipogenic markers in response to short-term brain ER stress (e.g. Pepck 2.45±0.24 fold vehicle; p<0.05). Second, male C57Bl/6 mice were fed high fat diet (HFD, 60% fat, n=8), a model that causes NAFLD and brain ER stress, or remained on normal chow (5% fat, n=6) for 20 weeks. ICV cannula were then implanted for delivery of the chemical ER chaperone TUDCA (5 μg/day) or vehicle control. Inhibition of brain ER stress with ICV TUDCA over 3 days rescued HFD-induced hepatomegaly (2.2±0.2 vs. 1.5±0.1 g; HFD vehicle vs. HFD TUDCA; p<0.05) and reduced obesity-induced liver triglyceride accumulation (365±44 vs. 127±36 mmol; HFD vehicle vs. HFD TUDCA; p<0.05), independent of changes in body weight, food intake or adiposity. These data demonstrate that induction of brain ER stress caused a NAFLD phenotype, whereas inhibition of chronic HFD-induced brain ER stress reduced hepatomegaly and hepatic steatosis. Collectively, these findings illustrate a novel role for ER stress in the brain as a contributor to NAFLD. HL63887, HL84207, AHA13POST14410020, K99HL166776
Author Disclosures: J.A. Horwath: None. F.N. Dong: None. S.D. Butler: None. A.L. Mark: None. R.L. Davisson: None. C.N. Young: None.
This research has received full or partial funding support from the American Heart Association, Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).
- © 2014 by American Heart Association, Inc.