Non-alcoholic fatty liver disease (NAFLD) is a major risk factor for the development of cardiovascular diseases (CVD), including hypertension. While most studies have focused on peripheral mechanisms mediating hepatic dysfunction, a role for the central nervous system in the pathogenesis of NAFLD is less appreciated. Here we tested the hypothesis that endoplasmic reticulum (ER) stress in the brain contributes to the development of NAFLD. First, adult male C57Bl/6 mice were instrumented with an intracerebroventricular (ICV) cannula for administration of the ER stress inducer thapsigargin (TG; 1 μg/day; 3 days; n=5), or vehicle control (n=4), and allowed 1 week recovery. Short-term induction of ER stress in the brain, using TG, did not alter body weight (26±1 vs. 27±1 g; vehicle vs. TG; p<0.05), food intake or adiposity, but caused a ~20% increase in liver weight (1.04±0.5 vs. 1.25±0.07 g; vehicle vs. TG; p<0.05). ICV TG also elicited an increase in liver lipid droplet accumulation (0.074±0.002 vs. 0.665±0.060 droplets/cm2; vehicle vs. TG; p<0.05) and up-regulated hepatic gluconeogenic and lipogenic markers (e.g. Pepck mRNA 1.56±0.13 fold vehicle; p<0.05). Second, male C57Bl/6 mice either remained on normal chow (n=6) or were fed a high fat diet (HFD; n=8) for a period of 20 weeks, a condition that we and others have shown results in ER stress in the brain. Mice were then implanted with an ICV cannula for administration of the chemical ER chaperone TUDCA (5 μg/day), or vehicle control, and allowed 1 week of recovery. ICV TUDCA administration over 5 days rescued HFD-induced hepatomegaly (1.77±0.18 vs. 1.19±0.07 g; HFD vehicle vs. HFD TUDCA; p<0.05) and reduced obesity-induced liver triglyceride accumulation (365±44 vs. 127±36 mM; HFD vehicle vs. HFD TUDCA; p<0.05), such that HFD ICV TUDCA treated mice were not different from controls. These data demonstrate that induction of ER stress in the brain causes hepatic lipid accumulation, independent of changes in body weight, food intake and adiposity. Furthermore, inhibition of chronic brain ER stress reduces HFD-induced hepatomegaly and hepatic steatosis. Collectively these findings illustrate a novel role for brain ER stress as a contributor to a major risk factor for CVD, NAFLD.
HL63887, HL84207, AHA13POST14410020