The prevalence of GD in NAFLD is more elevated than reported in the general population. The factors independently associated with GD in NAFLD are different from those reported in the general population and vary according to the gender.
The DNA binding activity of FUS (also known as TLS), a nuclear pro-oncogene involved in multiple translocations, is regulated by BCR-ABL in a protein kinase CII (PKCII)-dependent manner. We show here that in normal myeloid progenitor cells FUS, although not visibly ubiquitinated, undergoes proteasomedependent degradation, whereas in BCR-ABL-expressing cells, degradation is suppressed by PKCII phosphorylation. Replacement of serine 256 with the phosphomimetic aspartic acid prevents proteasome-dependent proteolysis of FUS, while the serine-256-to-alanine FUS mutant is unstable and susceptible to degradation. Ectopic expression of the phosphomimetic S256D FUS mutant in granulocyte colony-stimulating factor-treated 32Dcl3 cells induces massive apoptosis and inhibits the differentiation of the cells escaping cell death, while the degradation-prone S256A mutant has no effect on either survival or differentiation. FUS proteolysis is induced by c-Jun, is suppressed by BCR-ABL or Jun kinase 1, and does not depend on c-Jun transactivation potential, ubiquitination, or its interaction with Jun kinase 1. In addition, c-Jun-induced FUS proteasome-dependent degradation is enhanced by heterogeneous nuclear ribonucleoprotein (hnRNP) A1 and depends on the formation of a FUS-Jun-hnRNP A1-containing complex and on lack of PKCII phosphorylation at serine 256 but not on FUS ubiquitination. Thus, novel mechanisms appear to be involved in the degradation of FUS in normal myeloid cells; moreover, the ability of the BCR-ABL oncoprotein to suppress FUS degradation by the induction of posttranslational modifications might contribute to the phenotype of BCR-ABL-expressing hematopoietic cells.FUS, also known as TLS or heterogeneous nuclear ribonucleoprotein (hnRNP) P2, was first discovered as the N-terminal part of a fusion with CHOP in myxoid liposarcoma carrying the t(12;16) translocation (8, 33) and was subsequently detected in different types of human myeloid leukemia (37), in which the C terminus of FUS is replaced by the DNA-binding domain of ERG (28). The C terminus of FUS is required for binding to pre-mRNA and mRNA, while the N terminus appears to function as a transcription activation domain (34).
SummaryHepatic steatosis may be both an adaptive phenomenon and an example of lipotoxicity. Its prevalence ranks in the same order of magnitude of insulin resistance in the general population. Studies support the finding that hepatic steatosis is secondary to insulin resistance and not vice versa. A steatotic liver will further contribute to the development of insulin resistance through impaired clearance of insulin from the portal blood, creating a vicious cycle. Insulin resistance is the leading force in the pathogenesis and natural history of non‐alcoholic fatty liver disease. Dysfunction of energetic homeostasis and the interaction of adiponectin, leptin and tumour necrosis factor‐α are key events in the pathogenesis of steatosis and insulin resistance. Insulin resistance represents the frame within which hepatic and extrahepatic non‐alcoholic fatty liver disease‐related clinical manifestations are to be anticipated and interpreted.
In this cohort, immunological therapy was initiated within the first months of disease. Surgery and hospitalization rates did not differ between patients from eastern and western Europe, although more western European patients received biological agents and were comparable to previous population-based inception cohorts.
SUMMARYMetabolic syndrome represents a common risk factor for premature cardiovascular disease and cancer whose core cluster includes diabetes, hypertension, dyslipidaemia and obesity. The liver is a target organ in metabolic syndrome patients in which it manifests itself with nonalcoholic fatty liver disease spanning steatosis through hepatocellular carcinoma via steatohepatitis and cirrhosis. Given that metabolic syndrome and non-alcoholic fatty liver disease affect the same insulin-resistant patients, not unexpectedly, there are amazing similarities between metabolic syndrome and non-alcoholic fatty liver disease in terms of prevalence, pathogenesis, clinical features and outcome. The available drug weaponry for metabolic syndrome includes aspirin, metformin, peroxisome proliferator-activated receptor agonists, statins, ACE (angiotensin I-converting enzyme) inhibitors and sartans, which are potentially or clinically useful also to the non-alcoholic fatty liver disease patient. Studies are needed to highlight the grey areas in this topic. Issues to be addressed include: diagnostic criteria for metabolic syndrome; nomenclature of non-alcoholic fatty liver disease; enlargement of the clinical spectrum and characterization of the prognosis of insulin resistance-related diseases; evaluation of the most specific clinical predictors of metabolic syndrome/non-alcoholic fatty liver disease and assessment of their variability over the time; characterization of the importance of new risk factors for metabolic syndrome with regard to the development and progression of non-alcoholic fatty liver disease.
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