GLP-1 Analogs Reduce Hepatocyte Steatosis and Improve Survival by Enhancing the Unfolded Protein Response and Promoting Macroautophagy

Nonalcoholic fatty liver disease (NAFLD) is a known outcome of hepatosteatosis. Free fatty acids (FFA) induce the unfolded protein response (UPR) or endoplasmic reticulum (ER) stress that may induce apoptosis. Recent data indicate ER stress to be a major player in the progression of fatty liver to more aggressive lesions. Autophagy on the other hand has been demonstrated to be protective against ER stress-induced cell death. We hypothesized that exendin-4 (GLP-1 analog) treatment of fat loaded hepatocytes can reduce steatosis by autophagy which leads to reduced ER stress-related hepatocyte apoptosis.Primary human hepatocytes were loaded with saturated, cis- and trans-unsaturated fatty acids (palmitic, oleic and elaidic acid respectively). Steatosis, induced with all three fatty acids, was significantly resolved after exendin-4 treatment. Exendin-4 sustained levels of GRP78 expression in fat-loaded cells when compared to untreated fat-loaded cells alone. In contrast, CHOP (C/EBP homologous protein); the penultimate protein that leads to ER stress-related cell death was significantly decreased by exendin-4 in hepatocytes loaded with fatty acids. Finally, exendin-4 in fat loaded hepatocytes clearly promoted gene products associated with macroautophagy as measured by enhanced production of both Beclin-1 and LC3B-II, markers for autophagy; and visualized by transmission electron microscopy (TEM). Similar observations were made in mouse liver lysates after mice were fed with high fat high fructose diet and treated with a long acting GLP-1 receptor agonist, liraglutide.GLP-1 proteins appear to protect hepatocytes from fatty acid-related death by prohibition of a dysfunctional ER stress response; and reduce fatty acid accumulation, by activation of both macro-and chaperone-mediated autophagy. These findings provide a novel role for GLP-1 proteins in halting the progression of more aggressive lesions from underlying steatosis in humans afflicted with NAFLD

Regulation of basal cellular physiology by the homeostatic unfolded protein response

The extensive membrane network of the endoplasmic reticulum (ER) is physically juxtaposed to and functionally entwined with essentially all other cellular compartments. Therefore, the ER must sense diverse and constantly changing physiological inputs so it can adjust its numerous functions to maintain cellular homeostasis. A growing body of new work suggests that the unfolded protein response (UPR), traditionally charged with signaling protein misfolding stress from the ER, has been co-opted for the maintenance of basal cellular homeostasis. Thus, the UPR can be activated, and its output modulated, by signals far outside the realm of protein misfolding. These findings are revealing that the UPR causally contributes to disease not just by its role in protein folding but also through its broad influence on cellular physiology

Recurrent Blindness in an 11-Year Old Boy

Headache; Decreased central vision OSAn 11-year old male with headache and subsequent sudden onset of decreased central vision OS accompanied by pain associated with movement.VA: 20/20 OD, 3/400 OSOrbital inflammationSteroids; Anti-bacterial agents; SurgeryCForbitalmanifestationsofinflammatio

ASSESSMENT OF FUNCTIONAL STRENGTH, SIMULATED WORK-ACTIVITIES, EXERCISE EFFICIENCY, AND CARDIORESPIRATORY CAPACITY IN RAPPEL FIREFIGHTERS

J. Taylor, J. Morgan, D. Dutto, K. Pfaffenbach Eastern Oregon University, La Grande, OR. Wildland Rappel Firefighters are a unique task force responsible for forest fire ‘initial attack’. Briefly, at the outset of a wildfire, rappellers are dispatched via helicopter to the site of the burn. They descend from ropes out of the helicopter into the area of the blaze and set about to control the burn. Initial fire control requires arduous physical labor and can last 8 to 24 hours. Firefighters are then tasked with maintenance that last between 24-72 hours. From there, rappellers are responsible to for extraditing themselves from the backcountry via a ‘pack out’. Pack outs require hiking on undulating terrain, often without trail, with a 50kg pack across distances ranging from 8-16km. Despite the unique physical demands of this group of firefighters, little is known regarding the range of strength and fitness across the heterogenous population of firefighters. PURPOSE: The purpose of the current study is to better understand the baseline strength and cardiorespiratory capacity of a group of rappel firefighters. By understanding the unique strength and metabolic characteristics of each firefighters will allow for the development of individualized training programs. METHODS: Firefighters from the Grande Ronde Rapellers crew participated (n=14, age=33.5±4.27 years). Strength assessments included deadlift, 4.5kg medball throw, and a step test with 34kg pack at 120bpm/foot strike. Cardiorespiratory and exercise efficiency were assessed using open air spirometry gas analysis at various exercise intensities. Treadmill speed was set at 5.63kmh and subjects completed 5 minutes at 0.5% incline, 10% incline, 0.5% incline with 34kg pack, and 10% grade with pack. VO2 max was assessed with graded exercise test RESULTS: Mean and range for calculated deadlift max was 122.94±31.85kg and 81.82 - 193.18kg. Med Ball throw mean and range was 775.1±285.80Watts and 440-1149watts. Mean VO2 max was 44.16±6.02ml/kg/min. We observed substantial variation in exercise requirements in the inclined conditions. For example, average HR during inclined walking ranged 129.7-179.7bpm. Similarly, average HR varied during weighted incline walking from 156.3bpm to 199.7bpm. CONCLUSION: Despite having the same work demands, there is substantial variability between rappel firefighters in the strength and cardiorespiratory capacity

Spontaneous H-2 mutants provide evidence that a copy mechanism analogous to gene conversion generates polymorphism in the major histocompatibility complex.

The analysis of H-2K products from spontaneously generated major histocompatibility complex (MHC) mutants and of the primary structure of other class I antigens suggests the genetic hypothesis that diversity in the MHC results from a copy mechanism analogous to gene conversion. The hypothesis was tested by making precise structural predictions about three partially characterized MHC mutants (bm1, bm3, and bm8). The predictions were based on consensus sequences among class I genes that differ from H-2Kb in the same region of the molecule as do the Kb mutants. In two cases (bm3 and bm8) we successfully predicted the correct amino acid substitution at positions known to be altered but for which the specific nature of the substitution had not been determined. In two additional cases (bm1 and bm8) we predicted and found both new mutation sites and the specific amino acid substitutions. The positions and identifications of the variant amino acids were determined by radiolabeled amino acid sequence analysis and DNA restriction endonuclease analysis. The interaction of MHC genes through a copy mechanism to generate diversity permits the introduction of multiple nucleotide base substitutions into class I sequences by a single genetic event. Such a mechanism may account in part for the large structural divergence among alleles of MHC loci and the high degree of MHC polymorphism among wild mice