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

Drug Adverse Reactions Leading To Hospital Admission [reações Adversas A Medicamentos Como Determinantes Da Admissão Hospitalar.]

BACKGROUND: Few studies have addressed how often adverse drug reactions cause hospital admissions in Brazil. This study was carried out in a university hospital looking for the patterns of drug utilization before hospital admission and the frequency of adverse drug reactions. METHODS: The study was developed in two steps. The first step evaluated the hospital admission morbidity patterns at an Internal Medicine ward during 1997, using the hospital register system. The second step was carried out in 1999 when a hospital-based intensive monitoring program was performed during a 4 months period. Patients admitted to this ward were interviewed for the drugs used during 15 days before admission, their morbidity patterns were described in detail, and the possibility of adverse drug reactions being the cause of hospital admission was evaluated. RESULTS: During 1997, of the 938 patients admitted to the Internal Medicine ward, 46.6% were female patients, and a mean of 1.1 diagnosis per hospital admission was recorded. No adverse drug reaction was found. During the hospital-based intensive monitoring, of the 135 patients studied, 52% were female, 92% had used at least one drug before the hospital admission, and 42% had used self-medication. The mean of utilized drug was 3.7. Adverse drug reaction was the cause of or contributed to 6.6% of the hospital admissions. CONCLUSIONS: Hospital-based intensive monitoring stimulates the reporting of drug adverse reactions and is an important resource for training in rational drug use.48323724

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